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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
Structural studies of symmetric homo-oligomers provide mechanistic insights into their roles in essential biological processes, including cell signaling and cellular regulation. This paper presents a novel algorithm for homo-oligomeric structure determination, given the subunit structure, that is both complete, in that it evaluates all possible conformations, and data-driven, in that it evaluates conformations separately for consistency with experimental data and for quality of packing. Completeness ensures that the algorithm does not miss the native conformation, and being data-driven enables it to assess the structural precision possible from data alone. Our algorithm performs a branch-and-bound search in the symmetry configuration space, the space of symmetry axis parameters (positions and orientations) defining all possible C(n) homo-oligomeric complexes for a given subunit structure. It eliminates those symmetry axes inconsistent with intersubunit nuclear Overhauser effect (NOE) distance restraints and then identifies conformations representing any consistent, well-packed structure to within a user-defined similarity level.For the human phospholamban pentamer in dodecylphosphocholine micelles, using the structure of one subunit determined from a subset of the experimental NMR data, our algorithm identifies a diverse set of complex structures consistent with the nine intersubunit NOE restraints. The distribution of determined structures provides an objective characterization of structural uncertainty: backbone RMSD to the previously determined structure ranges from 1.07 to 8.85 A, and variance in backbone atomic coordinates is an average of 12.32 A(2). Incorporating vdW packing reduces structural diversity to a maximum backbone RMSD of 6.24 A and an average backbone variance of 6.80 A(2). By comparing data consistency and packing quality under different assumptions of oligomeric number, our algorithm identifies the pentamer as the most likely oligomeric state of phospholamban, demonstrating that it is possible to determine the oligomeric number directly from NMR data. Additional tests on a number of homo-oligomers, from dimer to heptamer, similarly demonstrate the power of our method to provide unbiased determination and evaluation of homo-oligomeric complex structures.
Structure determination of symmetric homo-oligomers by a complete search of symmetry configuration space, using NMR restraints and van der Waals packing.,Potluri S, Yan AK, Chou JJ, Donald BR, Bailey-Kellogg C Proteins. 2006 Oct 1;65(1):203-19. PMID:16897780[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ 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
- ↑ 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
- ↑ 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
- ↑ Potluri S, Yan AK, Chou JJ, Donald BR, Bailey-Kellogg C. Structure determination of symmetric homo-oligomers by a complete search of symmetry configuration space, using NMR restraints and van der Waals packing. Proteins. 2006 Oct 1;65(1):203-19. PMID:16897780 doi:10.1002/prot.21091
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