2joa: Difference between revisions

New page: left|200px<br /><applet load="2joa" size="350" color="white" frame="true" align="right" spinBox="true" caption="2joa" /> '''HtrA1 bound to an optimized peptide: NMR ass...
 
No edit summary
 
(16 intermediate revisions by the same user not shown)
Line 1: Line 1:
[[Image:2joa.jpg|left|200px]]<br /><applet load="2joa" size="350" color="white" frame="true" align="right" spinBox="true"
caption="2joa" />
'''HtrA1 bound to an optimized peptide: NMR assignment of PDZ domain and ligand resonances'''<br />


==Overview==
==HtrA1 bound to an optimized peptide: NMR assignment of PDZ domain and ligand resonances==
High-temperature requirement A (HtrA) and its homologs contain a serine, protease domain followed by one or two PDZ domains. Bacterial HtrA, proteins and the mitochondrial protein HtrA2/Omi maintain cell function by, acting as both molecular chaperones and proteases to manage misfolded, proteins. The biological roles of the mammalian family members HtrA1 and, HtrA3 are less clear. We report a detailed structural and functional, analysis of the PDZ domains of human HtrA1 and HtrA3 using peptide, libraries and affinity assays to define specificity, structural studies to, view the molecular details of ligand recognition, and alanine scanning, mutagenesis to investigate the energetic contributions of individual, residues to ligand binding. In common with HtrA2/Omi, we show that the PDZ, domains of HtrA1 and HtrA3 recognize hydrophobic polypeptides, and while, C-terminal sequences are preferred, internal sequences are also, recognized. However, the details of the interactions differ, as different, domains rely on interactions with different residues within the ligand to, achieve high affinity binding. The results suggest that mammalian HtrA PDZ, domains interact with a broad range of hydrophobic binding partners. This, promiscuous specificity resembles that of bacterial HtrA family members, and suggests a similar function for recognizing misfolded polypeptides, with exposed hydrophobic sequences. Our results support a common, activation mechanism for the HtrA family, whereby hydrophobic peptides, bind to the PDZ domain and induce conformational changes that activate the, protease. Such a mechanism is well suited to proteases evolved for the, recognition and degradation of misfolded proteins.
<StructureSection load='2joa' size='340' side='right'caption='[[2joa]]' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[2joa]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JOA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2JOA FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=2joa FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2joa OCA], [https://pdbe.org/2joa PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2joa RCSB], [https://www.ebi.ac.uk/pdbsum/2joa PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2joa ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/HTRA1_HUMAN HTRA1_HUMAN] Variations in the promoter region of HTRA1 are the cause of susceptibility to age-related macular degeneration type 7 (ARMD7) [MIM:[https://omim.org/entry/610149 610149]. ARMD is the leading cause of vision loss and blindness among older individuals in the developed word. It is classified as either dry (nonneovascular) or wet (neovascular). ARMD7 is a wet form, in which new blood vessels form and break beneath the retina. This leakage causes permanent damage to surrounding retinal tissue, distorting and destroying central vision. Wet ARMD is more prevalent among Asians than Caucasians.<ref>PMID:17053108</ref> <ref>PMID:17053109</ref>  Defects in HTRA1 are the cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) [MIM:[https://omim.org/entry/600142 600142]. CARASIL is characterized by nonhypertensive cerebral small-vessel arteriopathy with subcortical infarcts, alopecia, and spondylosis, with an onset in early adulthood. On neuropathological examination, atherosclerosis associated with intimal thickening and dense collagen fibers, loss of vascular smooth-muscle cells, and hyaline degeneration of the tunica media has been observed in cerebral small arteries.<ref>PMID:19387015</ref>
== Function ==
[https://www.uniprot.org/uniprot/HTRA1_HUMAN HTRA1_HUMAN] Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin. HTRA1-generated fibronectin fragments further induce synovial cells to up-regulate MMP1 and MMP3 production. May also degrade proteoglycans, such as aggrecan, decorin and fibromodulin. Through cleavage of proteoglycans, may release soluble FGF-glycosaminoglycan complexes that promote the range and intensity of FGF signals in the extracellular space. Regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. Inhibits signaling mediated by TGF-beta family members. This activity requires the integrity of the catalytic site, although it is unclear whether TGF-beta proteins are themselves degraded. By acting on TGF-beta signaling, may regulate many physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, degrades TSC2, leading to the activation of TSC2 downstream targets.<ref>PMID:9852107</ref> <ref>PMID:16377621</ref> <ref>PMID:20671064</ref>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jo/2joa_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2joa ConSurf].
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
High-temperature requirement A (HtrA) and its homologs contain a serine protease domain followed by one or two PDZ domains. Bacterial HtrA proteins and the mitochondrial protein HtrA2/Omi maintain cell function by acting as both molecular chaperones and proteases to manage misfolded proteins. The biological roles of the mammalian family members HtrA1 and HtrA3 are less clear. We report a detailed structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3 using peptide libraries and affinity assays to define specificity, structural studies to view the molecular details of ligand recognition, and alanine scanning mutagenesis to investigate the energetic contributions of individual residues to ligand binding. In common with HtrA2/Omi, we show that the PDZ domains of HtrA1 and HtrA3 recognize hydrophobic polypeptides, and while C-terminal sequences are preferred, internal sequences are also recognized. However, the details of the interactions differ, as different domains rely on interactions with different residues within the ligand to achieve high affinity binding. The results suggest that mammalian HtrA PDZ domains interact with a broad range of hydrophobic binding partners. This promiscuous specificity resembles that of bacterial HtrA family members and suggests a similar function for recognizing misfolded polypeptides with exposed hydrophobic sequences. Our results support a common activation mechanism for the HtrA family, whereby hydrophobic peptides bind to the PDZ domain and induce conformational changes that activate the protease. Such a mechanism is well suited to proteases evolved for the recognition and degradation of misfolded proteins.


==About this Structure==
Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3.,Runyon ST, Zhang Y, Appleton BA, Sazinsky SL, Wu P, Pan B, Wiesmann C, Skelton NJ, Sidhu SS Protein Sci. 2007 Nov;16(11):2454-71. PMID:17962403<ref>PMID:17962403</ref>
2JOA is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JOA OCA].


==Reference==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
Structural and functional analysis of the PDZ domains of human HtrA1 and HtrA3., Runyon ST, Zhang Y, Appleton BA, Sazinsky SL, Wu P, Pan B, Wiesmann C, Skelton NJ, Sidhu SS, Protein Sci. 2007 Nov;16(11):2454-71. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=17962403 17962403]
</div>
<div class="pdbe-citations 2joa" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Appleton, B.A.]]
[[Category: Synthetic construct]]
[[Category: Pan, B.]]
[[Category: Appleton BA]]
[[Category: Runyon, S.T.]]
[[Category: Pan B]]
[[Category: Sazinksy, S.L.]]
[[Category: Runyon ST]]
[[Category: Sidhu, S.S.]]
[[Category: Sazinksy SL]]
[[Category: Skelton, N.J.]]
[[Category: Sidhu SS]]
[[Category: Wiesmann, C.]]
[[Category: Skelton NJ]]
[[Category: Wu, P.]]
[[Category: Wiesmann C]]
[[Category: Zhang, Y.]]
[[Category: Wu P]]
[[Category: beta-sandwich]]
[[Category: Zhang Y]]
[[Category: cyclically-permuted]]
[[Category: pdz]]
[[Category: protein binding]]
 
''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Jan 23 12:08:25 2008''

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA