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==Combinatorial Engineering of Proteolytically Resistant APPI Variants that Selectively Inhibit Human Kallikrein 6 for Cancer Therapy==
==Combinatorial Engineering of Proteolytically Resistant APPI Variants that Selectively Inhibit Human Kallikrein 6 for Cancer Therapy==
<StructureSection load='5nx3' size='340' side='right' caption='[[5nx3]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
<StructureSection load='5nx3' size='340' side='right'caption='[[5nx3]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5nx3]] is a 4 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NX3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NX3 FirstGlance]. <br>
<table><tr><td colspan='2'>[[5nx3]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5NX3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5NX3 FirstGlance]. <br>
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5nx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nx3 OCA], [http://pdbe.org/5nx3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nx3 RCSB], [http://www.ebi.ac.uk/pdbsum/5nx3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nx3 ProSAT]</span></td></tr>
</td></tr><tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">KLK6, PRSS18, PRSS9 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), APP, A4, AD1 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5nx3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5nx3 OCA], [http://pdbe.org/5nx3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5nx3 RCSB], [http://www.ebi.ac.uk/pdbsum/5nx3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5nx3 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
Line 10: Line 11:
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN]] Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>  Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with Also bind GPC1 in lipid rafts.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>  Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain (By similarity).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>  The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>  N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>  [[http://www.uniprot.org/uniprot/KLK6_HUMAN KLK6_HUMAN]] Serine protease which exhibits a preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position. Shows activity against amyloid precursor protein, myelin basic protein, gelatin, casein and extracellular matrix proteins such as fibronectin, laminin, vitronectin and collagen. Degrades alpha-synuclein and prevents its polymerization, indicating that it may be involved in the pathogenesis of Parkinson disease and other synucleinopathies. May be involved in regulation of axon outgrowth following spinal cord injury. Tumor cells treated with a neutralizing KLK6 antibody migrate less than control cells, suggesting a role in invasion and metastasis.<ref>PMID:12878203</ref> <ref>PMID:12928483</ref> <ref>PMID:15557757</ref> <ref>PMID:16987227</ref> <ref>PMID:16321973</ref> <ref>PMID:11983703</ref>   
[[http://www.uniprot.org/uniprot/A4_HUMAN A4_HUMAN]] Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>  Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with Also bind GPC1 in lipid rafts.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>  Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain (By similarity).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>  The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>  N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).<ref>PMID:9168929</ref> <ref>PMID:11544248</ref> <ref>PMID:11943163</ref> <ref>PMID:19225519</ref> <ref>PMID:19901339</ref>  [[http://www.uniprot.org/uniprot/KLK6_HUMAN KLK6_HUMAN]] Serine protease which exhibits a preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position. Shows activity against amyloid precursor protein, myelin basic protein, gelatin, casein and extracellular matrix proteins such as fibronectin, laminin, vitronectin and collagen. Degrades alpha-synuclein and prevents its polymerization, indicating that it may be involved in the pathogenesis of Parkinson disease and other synucleinopathies. May be involved in regulation of axon outgrowth following spinal cord injury. Tumor cells treated with a neutralizing KLK6 antibody migrate less than control cells, suggesting a role in invasion and metastasis.<ref>PMID:12878203</ref> <ref>PMID:12928483</ref> <ref>PMID:15557757</ref> <ref>PMID:16987227</ref> <ref>PMID:16321973</ref> <ref>PMID:11983703</ref>   
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Human tissue kallikrein (KLK) proteases are hormone-like signaling molecules with important functions in cancer pathophysiology. KLK-related peptidase 6 (KLK6), specifically, is highly up-regulated in several types of cancer, where its increased activity promotes cancer invasion and metastasis. This characteristic suggests KLK6 as an attractive target for therapeutic interventions. However, inhibitors that specifically target KLK6 have not yet been reported, possibly because KLK6 shares a high sequence homology and structural similarity with other serine proteases and resists inhibition by many polypeptide inhibitors. Here, we present an innovative combinatorial approach to engineering KLK6 inhibitors via flow cytometry-based screening of a yeast-displayed mutant library of the human amyloid precursor protein Kunitz protease inhibitor domain (APPI), an inhibitor of other serine proteases, such as anionic and cationic trypsins. On the basis of this screening, we generated APPIM17L,I18F,S19F,F34V (APPI-4M), an APPI variant with a KLK6 inhibition constant (Ki ) of 160 pm and a turnover time of 10 days. To the best of our knowledge, APPI-4M is the most potent KLK6 inhibitor reported to date, displaying 146-fold improved affinity and 13-fold improved proteolytic stability compared with WT APPI (APPIWT). We further demonstrate that APPI-4M acts as a functional inhibitor in a cell-based model of KLK6-dependent breast cancer invasion. Finally, the crystal structures of the APPIWT/KLK6 and APPI-4M/KLK6 complexes revealed the structural and mechanistic bases for the improved KLK6 binding and proteolytic resistance of APPI-4M. We anticipate that APPI-4M will have substantial translational potential as both imaging agent and therapeutic.
A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering.,Sananes A, Cohen I, Shahar A, Hockla A, De Vita E, Miller AK, Radisky ES, Papo N J Biol Chem. 2018 Aug 17;293(33):12663-12680. doi: 10.1074/jbc.RA117.000871. Epub, 2018 Jun 22. PMID:29934309<ref>PMID:29934309</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5nx3" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
Line 17: Line 27:
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Papo, N]]
[[Category: Papo, N]]
[[Category: Radisky, E S]]
[[Category: Radisky, E S]]

Revision as of 09:05, 12 June 2019

Combinatorial Engineering of Proteolytically Resistant APPI Variants that Selectively Inhibit Human Kallikrein 6 for Cancer TherapyCombinatorial Engineering of Proteolytically Resistant APPI Variants that Selectively Inhibit Human Kallikrein 6 for Cancer Therapy

Structural highlights

5nx3 is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Gene:KLK6, PRSS18, PRSS9 (HUMAN), APP, A4, AD1 (HUMAN)
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[A4_HUMAN] Defects in APP are the cause of Alzheimer disease type 1 (AD1) [MIM:104300]. AD1 is a familial early-onset form of Alzheimer disease. It can be associated with cerebral amyloid angiopathy. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituent of these plaques is the neurotoxic amyloid-beta-APP 40-42 peptide (s), derived proteolytically from the transmembrane precursor protein APP by sequential secretase processing. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products such as C31 derived from APP, are also implicated in neuronal death.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] Defects in APP are the cause of cerebral amyloid angiopathy APP-related (CAA-APP) [MIM:605714]. A hereditary localized amyloidosis due to amyloid-beta A4 peptide(s) deposition in the cerebral vessels. The principal clinical characteristics are recurrent cerebral and cerebellar hemorrhages, recurrent strokes, cerebral ischemia, cerebral infarction, and progressive mental deterioration. Patients develop cerebral hemorrhage because of the severe cerebral amyloid angiopathy. Parenchymal amyloid deposits are rare and largely in the form of pre-amyloid lesions or diffuse plaque-like structures. They are Congo red negative and lack the dense amyloid cores commonly present in Alzheimer disease. Some affected individuals manifest progressive aphasic dementia, leukoencephalopathy, and occipital calcifications.[27] [28] [29] [30] [31]

Function

[A4_HUMAN] Functions as a cell surface receptor and performs physiological functions on the surface of neurons relevant to neurite growth, neuronal adhesion and axonogenesis. Involved in cell mobility and transcription regulation through protein-protein interactions. Can promote transcription activation through binding to APBB1-KAT5 and inhibits Notch signaling through interaction with Numb. Couples to apoptosis-inducing pathways such as those mediated by G(O) and JIP. Inhibits G(o) alpha ATPase activity (By similarity). Acts as a kinesin I membrane receptor, mediating the axonal transport of beta-secretase and presenilin 1. Involved in copper homeostasis/oxidative stress through copper ion reduction. In vitro, copper-metallated APP induces neuronal death directly or is potentiated through Cu(2+)-mediated low-density lipoprotein oxidation. Can regulate neurite outgrowth through binding to components of the extracellular matrix such as heparin and collagen I and IV. The splice isoforms that contain the BPTI domain possess protease inhibitor activity. Induces a AGER-dependent pathway that involves activation of p38 MAPK, resulting in internalization of amyloid-beta peptide and leading to mitochondrial dysfunction in cultured cortical neurons. Provides Cu(2+) ions for GPC1 which are required for release of nitric oxide (NO) and subsequent degradation of the heparan sulfate chains on GPC1.[32] [33] [34] [35] [36] Beta-amyloid peptides are lipophilic metal chelators with metal-reducing activity. Bind transient metals such as copper, zinc and iron. In vitro, can reduce Cu(2+) and Fe(3+) to Cu(+) and Fe(2+), respectively. Beta-amyloid 42 is a more effective reductant than beta-amyloid 40. Beta-amyloid peptides bind to lipoproteins and apolipoproteins E and J in the CSF and to HDL particles in plasma, inhibiting metal-catalyzed oxidation of lipoproteins. Beta-APP42 may activate mononuclear phagocytes in the brain and elicit inflammatory responses. Promotes both tau aggregation and TPK II-mediated phosphorylation. Interaction with Also bind GPC1 in lipid rafts.[37] [38] [39] [40] [41] Appicans elicit adhesion of neural cells to the extracellular matrix and may regulate neurite outgrowth in the brain (By similarity).[42] [43] [44] [45] [46] The gamma-CTF peptides as well as the caspase-cleaved peptides, including C31, are potent enhancers of neuronal apoptosis.[47] [48] [49] [50] [51] N-APP binds TNFRSF21 triggering caspase activation and degeneration of both neuronal cell bodies (via caspase-3) and axons (via caspase-6).[52] [53] [54] [55] [56] [KLK6_HUMAN] Serine protease which exhibits a preference for Arg over Lys in the substrate P1 position and for Ser or Pro in the P2 position. Shows activity against amyloid precursor protein, myelin basic protein, gelatin, casein and extracellular matrix proteins such as fibronectin, laminin, vitronectin and collagen. Degrades alpha-synuclein and prevents its polymerization, indicating that it may be involved in the pathogenesis of Parkinson disease and other synucleinopathies. May be involved in regulation of axon outgrowth following spinal cord injury. Tumor cells treated with a neutralizing KLK6 antibody migrate less than control cells, suggesting a role in invasion and metastasis.[57] [58] [59] [60] [61] [62]

Publication Abstract from PubMed

Human tissue kallikrein (KLK) proteases are hormone-like signaling molecules with important functions in cancer pathophysiology. KLK-related peptidase 6 (KLK6), specifically, is highly up-regulated in several types of cancer, where its increased activity promotes cancer invasion and metastasis. This characteristic suggests KLK6 as an attractive target for therapeutic interventions. However, inhibitors that specifically target KLK6 have not yet been reported, possibly because KLK6 shares a high sequence homology and structural similarity with other serine proteases and resists inhibition by many polypeptide inhibitors. Here, we present an innovative combinatorial approach to engineering KLK6 inhibitors via flow cytometry-based screening of a yeast-displayed mutant library of the human amyloid precursor protein Kunitz protease inhibitor domain (APPI), an inhibitor of other serine proteases, such as anionic and cationic trypsins. On the basis of this screening, we generated APPIM17L,I18F,S19F,F34V (APPI-4M), an APPI variant with a KLK6 inhibition constant (Ki ) of 160 pm and a turnover time of 10 days. To the best of our knowledge, APPI-4M is the most potent KLK6 inhibitor reported to date, displaying 146-fold improved affinity and 13-fold improved proteolytic stability compared with WT APPI (APPIWT). We further demonstrate that APPI-4M acts as a functional inhibitor in a cell-based model of KLK6-dependent breast cancer invasion. Finally, the crystal structures of the APPIWT/KLK6 and APPI-4M/KLK6 complexes revealed the structural and mechanistic bases for the improved KLK6 binding and proteolytic resistance of APPI-4M. We anticipate that APPI-4M will have substantial translational potential as both imaging agent and therapeutic.

A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering.,Sananes A, Cohen I, Shahar A, Hockla A, De Vita E, Miller AK, Radisky ES, Papo N J Biol Chem. 2018 Aug 17;293(33):12663-12680. doi: 10.1074/jbc.RA117.000871. Epub, 2018 Jun 22. PMID:29934309[63]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ Denman RB, Rosenzcwaig R, Miller DL. A system for studying the effect(s) of familial Alzheimer disease mutations on the processing of the beta-amyloid peptide precursor. Biochem Biophys Res Commun. 1993 Apr 15;192(1):96-103. PMID:8476439 doi:http://dx.doi.org/10.1006/bbrc.1993.1386
  2. ↑ Wakutani Y, Watanabe K, Adachi Y, Wada-Isoe K, Urakami K, Ninomiya H, Saido TC, Hashimoto T, Iwatsubo T, Nakashima K. Novel amyloid precursor protein gene missense mutation (D678N) in probable familial Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004 Jul;75(7):1039-42. PMID:15201367
  3. ↑ Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L, et al.. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature. 1991 Feb 21;349(6311):704-6. PMID:1671712 doi:http://dx.doi.org/10.1038/349704a0
  4. ↑ Yoshioka K, Miki T, Katsuya T, Ogihara T, Sakaki Y. The 717Val----Ile substitution in amyloid precursor protein is associated with familial Alzheimer's disease regardless of ethnic groups. Biochem Biophys Res Commun. 1991 Aug 15;178(3):1141-6. PMID:1908231
  5. ↑ Naruse S, Igarashi S, Kobayashi H, Aoki K, Inuzuka T, Kaneko K, Shimizu T, Iihara K, Kojima T, Miyatake T, et al.. Mis-sense mutation Val----Ile in exon 17 of amyloid precursor protein gene in Japanese familial Alzheimer's disease. Lancet. 1991 Apr 20;337(8747):978-9. PMID:1678058
  6. ↑ Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J, et al.. Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene. Nature. 1991 Oct 31;353(6347):844-6. PMID:1944558 doi:http://dx.doi.org/10.1038/353844a0
  7. ↑ Murrell J, Farlow M, Ghetti B, Benson MD. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science. 1991 Oct 4;254(5028):97-9. PMID:1925564
  8. ↑ Kamino K, Orr HT, Payami H, Wijsman EM, Alonso ME, Pulst SM, Anderson L, O'dahl S, Nemens E, White JA, et al.. Linkage and mutational analysis of familial Alzheimer disease kindreds for the APP gene region. Am J Hum Genet. 1992 Nov;51(5):998-1014. PMID:1415269
  9. ↑ Hendriks L, van Duijn CM, Cras P, Cruts M, Van Hul W, van Harskamp F, Warren A, McInnis MG, Antonarakis SE, Martin JJ, et al.. Presenile dementia and cerebral haemorrhage linked to a mutation at codon 692 of the beta-amyloid precursor protein gene. Nat Genet. 1992 Jun;1(3):218-21. PMID:1303239 doi:http://dx.doi.org/10.1038/ng0692-218
  10. ↑ Mullan M, Crawford F, Axelman K, Houlden H, Lilius L, Winblad B, Lannfelt L. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid. Nat Genet. 1992 Aug;1(5):345-7. PMID:1302033 doi:http://dx.doi.org/10.1038/ng0892-345
  11. ↑ Carter DA, Desmarais E, Bellis M, Campion D, Clerget-Darpoux F, Brice A, Agid Y, Jaillard-Serradt A, Mallet J. More missense in amyloid gene. Nat Genet. 1992 Dec;2(4):255-6. PMID:1303275 doi:http://dx.doi.org/10.1038/ng1292-255
  12. ↑ Liepnieks JJ, Ghetti B, Farlow M, Roses AD, Benson MD. Characterization of amyloid fibril beta-peptide in familial Alzheimer's disease with APP717 mutations. Biochem Biophys Res Commun. 1993 Dec 15;197(2):386-92. PMID:8267572
  13. ↑ Farlow M, Murrell J, Ghetti B, Unverzagt F, Zeldenrust S, Benson M. Clinical characteristics in a kindred with early-onset Alzheimer's disease and their linkage to a G-->T change at position 2149 of the amyloid precursor protein gene. Neurology. 1994 Jan;44(1):105-11. PMID:8290042
  14. ↑ Brooks WS, Martins RN, De Voecht J, Nicholson GA, Schofield PR, Kwok JB, Fisher C, Yeung LU, Van Broeckhoven C. A mutation in codon 717 of the amyloid precursor protein gene in an Australian family with Alzheimer's disease. Neurosci Lett. 1995 Oct 27;199(3):183-6. PMID:8577393
  15. ↑ Eckman CB, Mehta ND, Crook R, Perez-tur J, Prihar G, Pfeiffer E, Graff-Radford N, Hinder P, Yager D, Zenk B, Refolo LM, Prada CM, Younkin SG, Hutton M, Hardy J. A new pathogenic mutation in the APP gene (I716V) increases the relative proportion of A beta 42(43). Hum Mol Genet. 1997 Nov;6(12):2087-9. PMID:9328472
  16. ↑ Cras P, van Harskamp F, Hendriks L, Ceuterick C, van Duijn CM, Stefanko SZ, Hofman A, Kros JM, Van Broeckhoven C, Martin JJ. Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala-->Gly mutation. Acta Neuropathol. 1998 Sep;96(3):253-60. PMID:9754958
  17. ↑ Ancolio K, Dumanchin C, Barelli H, Warter JM, Brice A, Campion D, Frebourg T, Checler F. Unusual phenotypic alteration of beta amyloid precursor protein (betaAPP) maturation by a new Val-715 --> Met betaAPP-770 mutation responsible for probable early-onset Alzheimer's disease. Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):4119-24. PMID:10097173
  18. ↑ Finckh U, Muller-Thomsen T, Mann U, Eggers C, Marksteiner J, Meins W, Binetti G, Alberici A, Hock C, Nitsch RM, Gal A. High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes. Am J Hum Genet. 2000 Jan;66(1):110-7. PMID:10631141 doi:S0002-9297(07)62237-X
  19. ↑ Kwok JB, Li QX, Hallupp M, Whyte S, Ames D, Beyreuther K, Masters CL, Schofield PR. Novel Leu723Pro amyloid precursor protein mutation increases amyloid beta42(43) peptide levels and induces apoptosis. Ann Neurol. 2000 Feb;47(2):249-53. PMID:10665499
  20. ↑ Murrell JR, Hake AM, Quaid KA, Farlow MR, Ghetti B. Early-onset Alzheimer disease caused by a new mutation (V717L) in the amyloid precursor protein gene. Arch Neurol. 2000 Jun;57(6):885-7. PMID:10867787
  21. ↑ Kumar-Singh S, De Jonghe C, Cruts M, Kleinert R, Wang R, Mercken M, De Strooper B, Vanderstichele H, Lofgren A, Vanderhoeven I, Backhovens H, Vanmechelen E, Kroisel PM, Van Broeckhoven C. Nonfibrillar diffuse amyloid deposition due to a gamma(42)-secretase site mutation points to an essential role for N-truncated A beta(42) in Alzheimer's disease. Hum Mol Genet. 2000 Nov 1;9(18):2589-98. PMID:11063718
  22. ↑ Walsh DM, Hartley DM, Condron MM, Selkoe DJ, Teplow DB. In vitro studies of amyloid beta-protein fibril assembly and toxicity provide clues to the aetiology of Flemish variant (Ala692-->Gly) Alzheimer's disease. Biochem J. 2001 May 1;355(Pt 3):869-77. PMID:11311152
  23. ↑ Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Naslund J, Lannfelt L. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001 Sep;4(9):887-93. PMID:11528419 doi:10.1038/nn0901-887
  24. ↑ Pasalar P, Najmabadi H, Noorian AR, Moghimi B, Jannati A, Soltanzadeh A, Krefft T, Crook R, Hardy J. An Iranian family with Alzheimer's disease caused by a novel APP mutation (Thr714Ala). Neurology. 2002 May 28;58(10):1574-5. PMID:12034808
  25. ↑ Rossi G, Giaccone G, Maletta R, Morbin M, Capobianco R, Mangieri M, Giovagnoli AR, Bizzi A, Tomaino C, Perri M, Di Natale M, Tagliavini F, Bugiani O, Bruni AC. A family with Alzheimer disease and strokes associated with A713T mutation of the APP gene. Neurology. 2004 Sep 14;63(5):910-2. PMID:15365148
  26. ↑ Edwards-Lee T, Ringman JM, Chung J, Werner J, Morgan A, St George Hyslop P, Thompson P, Dutton R, Mlikotic A, Rogaeva E, Hardy J. An African American family with early-onset Alzheimer disease and an APP (T714I) mutation. Neurology. 2005 Jan 25;64(2):377-9. PMID:15668448 doi:64/2/377
  27. ↑ Miravalle L, Tokuda T, Chiarle R, Giaccone G, Bugiani O, Tagliavini F, Frangione B, Ghiso J. Substitutions at codon 22 of Alzheimer's abeta peptide induce diverse conformational changes and apoptotic effects in human cerebral endothelial cells. J Biol Chem. 2000 Sep 1;275(35):27110-6. PMID:10821838 doi:10.1074/jbc.M003154200
  28. ↑ Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, Bots GT, Luyendijk W, Frangione B. Mutation of the Alzheimer's disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science. 1990 Jun 1;248(4959):1124-6. PMID:2111584
  29. ↑ Grabowski TJ, Cho HS, Vonsattel JP, Rebeck GW, Greenberg SM. Novel amyloid precursor protein mutation in an Iowa family with dementia and severe cerebral amyloid angiopathy. Ann Neurol. 2001 Jun;49(6):697-705. PMID:11409420
  30. ↑ Greenberg SM, Shin Y, Grabowski TJ, Cooper GE, Rebeck GW, Iglesias S, Chapon F, Tournier-Lasserve E, Baron JC. Hemorrhagic stroke associated with the Iowa amyloid precursor protein mutation. Neurology. 2003 Mar 25;60(6):1020-2. PMID:12654973
  31. ↑ Obici L, Demarchi A, de Rosa G, Bellotti V, Marciano S, Donadei S, Arbustini E, Palladini G, Diegoli M, Genovese E, Ferrari G, Coverlizza S, Merlini G. A novel AbetaPP mutation exclusively associated with cerebral amyloid angiopathy. Ann Neurol. 2005 Oct;58(4):639-44. PMID:16178030 doi:10.1002/ana.20571
  32. ↑ Walter MF, Mason PE, Mason RP. Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem Biophys Res Commun. 1997 Apr 28;233(3):760-4. PMID:9168929 doi:10.1006/bbrc.1997.6547
  33. ↑ Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem. 2001 Oct 26;276(43):40288-92. Epub 2001 Sep 5. PMID:11544248 doi:10.1074/jbc.C100447200
  34. ↑ Rank KB, Pauley AM, Bhattacharya K, Wang Z, Evans DB, Fleck TJ, Johnston JA, Sharma SK. Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II. FEBS Lett. 2002 Mar 13;514(2-3):263-8. PMID:11943163
  35. ↑ Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767
  36. ↑ Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20021-6. doi:, 10.1073/pnas.0905686106. Epub 2009 Nov 9. PMID:19901339 doi:10.1073/pnas.0905686106
  37. ↑ Walter MF, Mason PE, Mason RP. Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem Biophys Res Commun. 1997 Apr 28;233(3):760-4. PMID:9168929 doi:10.1006/bbrc.1997.6547
  38. ↑ Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem. 2001 Oct 26;276(43):40288-92. Epub 2001 Sep 5. PMID:11544248 doi:10.1074/jbc.C100447200
  39. ↑ Rank KB, Pauley AM, Bhattacharya K, Wang Z, Evans DB, Fleck TJ, Johnston JA, Sharma SK. Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II. FEBS Lett. 2002 Mar 13;514(2-3):263-8. PMID:11943163
  40. ↑ Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767
  41. ↑ Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20021-6. doi:, 10.1073/pnas.0905686106. Epub 2009 Nov 9. PMID:19901339 doi:10.1073/pnas.0905686106
  42. ↑ Walter MF, Mason PE, Mason RP. Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem Biophys Res Commun. 1997 Apr 28;233(3):760-4. PMID:9168929 doi:10.1006/bbrc.1997.6547
  43. ↑ Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem. 2001 Oct 26;276(43):40288-92. Epub 2001 Sep 5. PMID:11544248 doi:10.1074/jbc.C100447200
  44. ↑ Rank KB, Pauley AM, Bhattacharya K, Wang Z, Evans DB, Fleck TJ, Johnston JA, Sharma SK. Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II. FEBS Lett. 2002 Mar 13;514(2-3):263-8. PMID:11943163
  45. ↑ Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767
  46. ↑ Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20021-6. doi:, 10.1073/pnas.0905686106. Epub 2009 Nov 9. PMID:19901339 doi:10.1073/pnas.0905686106
  47. ↑ Walter MF, Mason PE, Mason RP. Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem Biophys Res Commun. 1997 Apr 28;233(3):760-4. PMID:9168929 doi:10.1006/bbrc.1997.6547
  48. ↑ Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem. 2001 Oct 26;276(43):40288-92. Epub 2001 Sep 5. PMID:11544248 doi:10.1074/jbc.C100447200
  49. ↑ Rank KB, Pauley AM, Bhattacharya K, Wang Z, Evans DB, Fleck TJ, Johnston JA, Sharma SK. Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II. FEBS Lett. 2002 Mar 13;514(2-3):263-8. PMID:11943163
  50. ↑ Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767
  51. ↑ Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20021-6. doi:, 10.1073/pnas.0905686106. Epub 2009 Nov 9. PMID:19901339 doi:10.1073/pnas.0905686106
  52. ↑ Walter MF, Mason PE, Mason RP. Alzheimer's disease amyloid beta peptide 25-35 inhibits lipid peroxidation as a result of its membrane interactions. Biochem Biophys Res Commun. 1997 Apr 28;233(3):760-4. PMID:9168929 doi:10.1006/bbrc.1997.6547
  53. ↑ Kimberly WT, Zheng JB, Guenette SY, Selkoe DJ. The intracellular domain of the beta-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a notch-like manner. J Biol Chem. 2001 Oct 26;276(43):40288-92. Epub 2001 Sep 5. PMID:11544248 doi:10.1074/jbc.C100447200
  54. ↑ Rank KB, Pauley AM, Bhattacharya K, Wang Z, Evans DB, Fleck TJ, Johnston JA, Sharma SK. Direct interaction of soluble human recombinant tau protein with Abeta 1-42 results in tau aggregation and hyperphosphorylation by tau protein kinase II. FEBS Lett. 2002 Mar 13;514(2-3):263-8. PMID:11943163
  55. ↑ Nikolaev A, McLaughlin T, O'Leary DD, Tessier-Lavigne M. APP binds DR6 to trigger axon pruning and neuron death via distinct caspases. Nature. 2009 Feb 19;457(7232):981-9. PMID:19225519 doi:10.1038/nature07767
  56. ↑ Takuma K, Fang F, Zhang W, Yan S, Fukuzaki E, Du H, Sosunov A, McKhann G, Funatsu Y, Nakamichi N, Nagai T, Mizoguchi H, Ibi D, Hori O, Ogawa S, Stern DM, Yamada K, Yan SS. RAGE-mediated signaling contributes to intraneuronal transport of amyloid-beta and neuronal dysfunction. Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):20021-6. doi:, 10.1073/pnas.0905686106. Epub 2009 Nov 9. PMID:19901339 doi:10.1073/pnas.0905686106
  57. ↑ Magklara A, Mellati AA, Wasney GA, Little SP, Sotiropoulou G, Becker GW, Diamandis EP. Characterization of the enzymatic activity of human kallikrein 6: Autoactivation, substrate specificity, and regulation by inhibitors. Biochem Biophys Res Commun. 2003 Aug 8;307(4):948-55. PMID:12878203
  58. ↑ Iwata A, Maruyama M, Akagi T, Hashikawa T, Kanazawa I, Tsuji S, Nukina N. Alpha-synuclein degradation by serine protease neurosin: implication for pathogenesis of synucleinopathies. Hum Mol Genet. 2003 Oct 15;12(20):2625-35. Epub 2003 Aug 19. PMID:12928483 doi:http://dx.doi.org/10.1093/hmg/ddg283
  59. ↑ Ghosh MC, Grass L, Soosaipillai A, Sotiropoulou G, Diamandis EP. Human kallikrein 6 degrades extracellular matrix proteins and may enhance the metastatic potential of tumour cells. Tumour Biol. 2004 Jul-Aug;25(4):193-9. PMID:15557757 doi:http://dx.doi.org/10.1159/000081102
  60. ↑ Scarisbrick IA, Sabharwal P, Cruz H, Larsen N, Vandell AG, Blaber SI, Ameenuddin S, Papke LM, Fehlings MG, Reeves RK, Blaber M, Windebank AJ, Rodriguez M. Dynamic role of kallikrein 6 in traumatic spinal cord injury. Eur J Neurosci. 2006 Sep;24(5):1457-69. PMID:16987227 doi:http://dx.doi.org/10.1111/j.1460-9568.2006.05021.x
  61. ↑ Angelo PF, Lima AR, Alves FM, Blaber SI, Scarisbrick IA, Blaber M, Juliano L, Juliano MA. Substrate specificity of human kallikrein 6: salt and glycosaminoglycan activation effects. J Biol Chem. 2006 Feb 10;281(6):3116-26. Epub 2005 Dec 1. PMID:16321973 doi:http://dx.doi.org/M510096200
  62. ↑ Bernett MJ, Blaber SI, Scarisbrick IA, Dhanarajan P, Thompson SM, Blaber M. Crystal structure and biochemical characterization of human kallikrein 6 reveals that a trypsin-like kallikrein is expressed in the central nervous system. J Biol Chem. 2002 Jul 5;277(27):24562-70. Epub 2002 Apr 30. PMID:11983703 doi:10.1074/jbc.M202392200
  63. ↑ Sananes A, Cohen I, Shahar A, Hockla A, De Vita E, Miller AK, Radisky ES, Papo N. A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering. J Biol Chem. 2018 Aug 17;293(33):12663-12680. doi: 10.1074/jbc.RA117.000871. Epub, 2018 Jun 22. PMID:29934309 doi:http://dx.doi.org/10.1074/jbc.RA117.000871

5nx3, resolution 2.30Å

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