7e12: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older edit
No edit summary
No edit summary
 
Line 8: Line 8:
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7e12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e12 OCA], [https://pdbe.org/7e12 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e12 RCSB], [https://www.ebi.ac.uk/pdbsum/7e12 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e12 ProSAT]</span></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=7e12 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7e12 OCA], [https://pdbe.org/7e12 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7e12 RCSB], [https://www.ebi.ac.uk/pdbsum/7e12 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7e12 ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/PPLA_HUMAN PPLA_HUMAN] Defects in PLN are the cause of cardiomyopathy dilated type 1P (CMD1P) [MIM:[https://omim.org/entry/609909 609909]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.<ref>PMID:12610310</ref> <ref>PMID:16432188</ref>  Defects in PLN are the cause of familial hypertrophic cardiomyopathy type 18 (CMH18) [MIM:[https://omim.org/entry/613874 613874]. CMH18 is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.<ref>PMID:12705874</ref>
== Function ==
== Function ==
[https://www.uniprot.org/uniprot/KAPCA_MOUSE KAPCA_MOUSE] Phosphorylates a large number of substrates in the cytoplasm and the nucleus. Regulates the abundance of compartmentalized pools of its regulatory subunits through phosphorylation of PJA2 which binds and ubiquitinates these subunits, leading to their subsequent proteolysis. Phosphorylates CDC25B, ABL1, NFKB1, CLDN3, PSMC5/RPT6, PJA2, RYR2, RORA, TRPC1 and VASP. RORA is activated by phosphorylation. Required for glucose-mediated adipogenic differentiation increase and osteogenic differentiation inhibition from osteoblasts. Involved in the regulation of platelets in response to thrombin and collagen; maintains circulating platelets in a resting state by phosphorylating proteins in numerous platelet inhibitory pathways when in complex with NF-kappa-B (NFKB1 and NFKB2) and I-kappa-B-alpha (NFKBIA), but thrombin and collagen disrupt these complexes and free active PRKACA stimulates platelets and leads to platelet aggregation by phosphorylating VASP. Prevents the antiproliferative and anti-invasive effects of alpha-difluoromethylornithine in breast cancer cells when activated. RYR2 channel activity is potentiated by phosphorylation in presence of luminal Ca(2+), leading to reduced amplitude and increased frequency of store overload-induced Ca(2+) release (SOICR) characterized by an increased rate of Ca(2+) release and propagation velocity of spontaneous Ca(2+) waves, despite reduced wave amplitude and resting cytosolic Ca(2+). TRPC1 activation by phosphorylation promotes Ca(2+) influx, essential for the increase in permeability induced by thrombin in confluent endothelial monolayers. PSMC5/RPT6 activation by phosphorylation stimulates proteasome. Regulates negatively tight junction (TJs) in ovarian cancer cells via CLDN3 phosphorylation. NFKB1 phosphorylation promotes NF-kappa-B p50-p50 DNA binding. Involved in embryonic development by down-regulating the Hedgehog (Hh) signaling pathway that determines embryo pattern formation and morphogenesis. Isoform 2 phosphorylates and activates ABL1 in sperm flagellum to promote spermatozoa capacitation. Prevents meiosis resumption in prophase-arrested oocytes via CDC25B inactivation by phosphorylation. May also regulate rapid eye movement (REM) sleep in the pedunculopontine tegmental (PPT).<ref>PMID:15340140</ref> <ref>PMID:19223768</ref> <ref>PMID:19560455</ref>  
[https://www.uniprot.org/uniprot/PPLA_HUMAN PPLA_HUMAN] Phospholamban has been postulated to regulate the activity of the calcium pump of cardiac sarcoplasmic reticulum.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Several mutations identified in phospholamban (PLN) have been linked to familial dilated cardiomyopathy (DCM) and heart failure, yet the underlying molecular mechanism remains controversial. PLN interacts with sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and regulates calcium uptake, which is modulated by the protein kinase A (PKA)-dependent phosphorylation of PLN during the fight-or-flight response. Here, we present the crystal structures of the catalytic domain of mouse PKA in complex with wild-type and DCM-mutant PLNs. Our structures, combined with the results from other biophysical and biochemical assays, reveal a common disease mechanism: the mutations in PLN reduce its phosphorylation level by changing its conformation and weakening its interactions with PKA. In addition, we demonstrate that another more ubiquitous SERCA-regulatory peptide, called another-regulin (ALN), shares a similar mechanism mediated by PKA in regulating SERCA activity.
 
Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy.,Qin J, Zhang J, Lin L, Haji-Ghassemi O, Lin Z, Woycechowsky KJ, Van Petegem F, Zhang Y, Yuchi Z Elife. 2022 Mar 17;11:e75346. doi: 10.7554/eLife.75346. PMID:35297759<ref>PMID:35297759</ref>
 
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7e12" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==

Latest revision as of 16:32, 6 November 2024

Crystal structure of PKAc-A11E complexCrystal structure of PKAc-A11E complex

Structural highlights

7e12 is a 2 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.796Å
Ligands:, , ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

PPLA_HUMAN Defects in PLN are the cause of cardiomyopathy dilated type 1P (CMD1P) [MIM:609909. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.[1] [2] Defects in PLN are the cause of familial hypertrophic cardiomyopathy type 18 (CMH18) [MIM:613874. CMH18 is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.[3]

Function

PPLA_HUMAN Phospholamban has been postulated to regulate the activity of the calcium pump of cardiac sarcoplasmic reticulum.

Publication Abstract from PubMed

Several mutations identified in phospholamban (PLN) have been linked to familial dilated cardiomyopathy (DCM) and heart failure, yet the underlying molecular mechanism remains controversial. PLN interacts with sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) and regulates calcium uptake, which is modulated by the protein kinase A (PKA)-dependent phosphorylation of PLN during the fight-or-flight response. Here, we present the crystal structures of the catalytic domain of mouse PKA in complex with wild-type and DCM-mutant PLNs. Our structures, combined with the results from other biophysical and biochemical assays, reveal a common disease mechanism: the mutations in PLN reduce its phosphorylation level by changing its conformation and weakening its interactions with PKA. In addition, we demonstrate that another more ubiquitous SERCA-regulatory peptide, called another-regulin (ALN), shares a similar mechanism mediated by PKA in regulating SERCA activity.

Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy.,Qin J, Zhang J, Lin L, Haji-Ghassemi O, Lin Z, Woycechowsky KJ, Van Petegem F, Zhang Y, Yuchi Z Elife. 2022 Mar 17;11:e75346. doi: 10.7554/eLife.75346. PMID:35297759[4]

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

See Also

References

  1. ↑ Schmitt JP, Kamisago M, Asahi M, Li GH, Ahmad F, Mende U, Kranias EG, MacLennan DH, Seidman JG, Seidman CE. Dilated cardiomyopathy and heart failure caused by a mutation in phospholamban. Science. 2003 Feb 28;299(5611):1410-3. PMID:12610310 doi:10.1126/science.1081578
  2. ↑ Haghighi K, Kolokathis F, Gramolini AO, Waggoner JR, Pater L, Lynch RA, Fan GC, Tsiapras D, Parekh RR, Dorn GW 2nd, MacLennan DH, Kremastinos DT, Kranias EG. A mutation in the human phospholamban gene, deleting arginine 14, results in lethal, hereditary cardiomyopathy. Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1388-93. Epub 2006 Jan 23. PMID:16432188 doi:10.1073/pnas.0510519103
  3. ↑ Minamisawa S, Sato Y, Tatsuguchi Y, Fujino T, Imamura S, Uetsuka Y, Nakazawa M, Matsuoka R. Mutation of the phospholamban promoter associated with hypertrophic cardiomyopathy. Biochem Biophys Res Commun. 2003 Apr 25;304(1):1-4. PMID:12705874
  4. ↑ Qin J, Zhang J, Lin L, Haji-Ghassemi O, Lin Z, Woycechowsky KJ, Van Petegem F, Zhang Y, Yuchi Z. Structures of PKA-phospholamban complexes reveal a mechanism of familial dilated cardiomyopathy. Elife. 2022 Mar 17;11:e75346. PMID:35297759 doi:10.7554/eLife.75346

7e12, resolution 2.80Å

Drag the structure with the mouse to rotate

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

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=7e12&oldid=4229363"