6b27

From Proteopedia

(Difference between revisions)

Revision as of 07:41, 8 November 2017

Crystal structure of human STAC2 Tandem SH3 Domains (296-411) in complex with a CaV1.1 II-III loop peptide

Structural highlights

6b27 is a 12 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	,
Gene:	STAC2 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[CAC1S_HUMAN] Defects in CACNA1S are the cause of periodic paralysis hypokalemic type 1 (HOKPP1) [MIM:170400]; also designated HYPOPP. HOKPP1 is an autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels.^[1] ^[2] ^[3] ^[4] ^[5] Genetic variations in CACNA1S are the cause of susceptibility to malignant hyperthermia 5 (MHS5) [MIM:601887]; an autosomal dominant disorder that is potentially lethal in susceptible individuals on exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants.^[6] Defects in CACNA1S are the cause of susceptibility to thyrotoxic periodic paralysis type 1 (TTPP1) [MIM:188580]. A sporadic muscular disorder characterized by episodic weakness and hypokalemia during a thyrotoxic state. It is clinically similar to hereditary hypokalemic periodic paralysis, except for the fact that hyperthyroidism is an absolute requirement for disease manifestation. The disease presents with recurrent episodes of acute muscular weakness of the four extremities that vary in severity from paresis to complete paralysis. Attacks are triggered by ingestion of a high carbohydrate load or strenuous physical activity followed by a period of rest. Thyrotoxic periodic paralysis can occur in association with any cause of hyperthyroidism, but is most commonly associated with Graves disease.^[7]

Function

[CAC1S_HUMAN] Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1S gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin-GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle.

Publication Abstract from PubMed

Excitation-contraction (EC) coupling in skeletal muscle requires functional and mechanical coupling between L-type voltage-gated calcium channels (CaV1.1) and the ryanodine receptor (RyR1). Recently, STAC3 was identified as an essential protein for EC coupling and is part of a group of three proteins that can bind and modulate L-type voltage-gated calcium channels. Here, we report crystal structures of tandem-SH3 domains of different STAC isoforms up to 1.2-A resolution. These form a rigid interaction through a conserved interdomain interface. We identify the linker connecting transmembrane repeats II and III in two different CaV isoforms as a binding site for the SH3 domains and report a crystal structure of the complex with the STAC2 isoform. The interaction site includes the location for a disease variant in STAC3 that has been linked to Native American myopathy (NAM). Introducing the mutation does not cause misfolding of the SH3 domains, but abolishes the interaction. Disruption of the interaction via mutations in the II-III loop perturbs skeletal muscle EC coupling, but preserves the ability of STAC3 to slow down inactivation of CaV1.2.

Structural insights into binding of STAC proteins to voltage-gated calcium channels.,Wong King Yuen SM, Campiglio M, Tung CC, Flucher BE, Van Petegem F Proc Natl Acad Sci U S A. 2017 Oct 23. pii: 201708852. doi:, 10.1073/pnas.1708852114. PMID:29078335^[8]

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

References

↑ Ptacek LJ, Tawil R, Griggs RC, Engel AG, Layzer RB, Kwiecinski H, McManis PG, Santiago L, Moore M, Fouad G, et al.. Dihydropyridine receptor mutations cause hypokalemic periodic paralysis. Cell. 1994 Jun 17;77(6):863-8. PMID:8004673
↑ Jurkat-Rott K, Lehmann-Horn F, Elbaz A, Heine R, Gregg RG, Hogan K, Powers PA, Lapie P, Vale-Santos JE, Weissenbach J, et al.. A calcium channel mutation causing hypokalemic periodic paralysis. Hum Mol Genet. 1994 Aug;3(8):1415-9. PMID:7987325
↑ Kim JB, Kim MH, Lee SJ, Kim DJ, Lee BC. The genotype and clinical phenotype of Korean patients with familial hypokalemic periodic paralysis. J Korean Med Sci. 2007 Dec;22(6):946-51. PMID:18162704
↑ Houinato D, Laleye A, Adjien C, Adjagba M, Sternberg D, Hilbert P, Vallat JM, Darboux RB, Funalot B, Avode DG. Hypokalaemic periodic paralysis due to the CACNA1S R1239H mutation in a large African family. Neuromuscul Disord. 2007 May;17(5):419-22. Epub 2007 Apr 5. PMID:17418573 doi:10.1016/j.nmd.2007.01.020
↑ Matthews E, Labrum R, Sweeney MG, Sud R, Haworth A, Chinnery PF, Meola G, Schorge S, Kullmann DM, Davis MB, Hanna MG. Voltage sensor charge loss accounts for most cases of hypokalemic periodic paralysis. Neurology. 2009 May 5;72(18):1544-7. Epub 2008 Dec 31. PMID:19118277 doi:01.wnl.0000342387.65477.46
↑ Monnier N, Procaccio V, Stieglitz P, Lunardi J. Malignant-hyperthermia susceptibility is associated with a mutation of the alpha 1-subunit of the human dihydropyridine-sensitive L-type voltage-dependent calcium-channel receptor in skeletal muscle. Am J Hum Genet. 1997 Jun;60(6):1316-25. PMID:9199552
↑ Kung AW, Lau KS, Fong GC, Chan V. Association of novel single nucleotide polymorphisms in the calcium channel alpha 1 subunit gene (Ca(v)1.1) and thyrotoxic periodic paralysis. J Clin Endocrinol Metab. 2004 Mar;89(3):1340-5. PMID:15001631
↑ Wong King Yuen SM, Campiglio M, Tung CC, Flucher BE, Van Petegem F. Structural insights into binding of STAC proteins to voltage-gated calcium channels. Proc Natl Acad Sci U S A. 2017 Oct 23. pii: 201708852. doi:, 10.1073/pnas.1708852114. PMID:29078335 doi:http://dx.doi.org/10.1073/pnas.1708852114

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6b27"

@@ Line 3: / Line 3: @@
 <StructureSection load='6b27' size='340' side='right' caption='[[6b27]], [[Resolution|resolution]] 1.73&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6b27]] is a 12 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B27 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B27 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6b27]] is a 12 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=6B27 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B27 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">STAC2 ([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=6b27 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b27 OCA], [http://pdbe.org/6b27 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b27 RCSB], [http://www.ebi.ac.uk/pdbsum/6b27 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b27 ProSAT]</span></td></tr>
 </table>
@@ Line 11: / Line 12: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/CAC1S_HUMAN CAC1S_HUMAN]] Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1S gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, benzothiazepines, and by omega-agatoxin-IIIA (omega-Aga-IIIA). They are however insensitive to omega-conotoxin-GVIA (omega-CTx-GVIA) and omega-agatoxin-IVA (omega-Aga-IVA). Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Excitation-contraction (EC) coupling in skeletal muscle requires functional and mechanical coupling between L-type voltage-gated calcium channels (CaV1.1) and the ryanodine receptor (RyR1). Recently, STAC3 was identified as an essential protein for EC coupling and is part of a group of three proteins that can bind and modulate L-type voltage-gated calcium channels. Here, we report crystal structures of tandem-SH3 domains of different STAC isoforms up to 1.2-A resolution. These form a rigid interaction through a conserved interdomain interface. We identify the linker connecting transmembrane repeats II and III in two different CaV isoforms as a binding site for the SH3 domains and report a crystal structure of the complex with the STAC2 isoform. The interaction site includes the location for a disease variant in STAC3 that has been linked to Native American myopathy (NAM). Introducing the mutation does not cause misfolding of the SH3 domains, but abolishes the interaction. Disruption of the interaction via mutations in the II-III loop perturbs skeletal muscle EC coupling, but preserves the ability of STAC3 to slow down inactivation of CaV1.2.
+Structural insights into binding of STAC proteins to voltage-gated calcium channels.,Wong King Yuen SM, Campiglio M, Tung CC, Flucher BE, Van Petegem F Proc Natl Acad Sci U S A. 2017 Oct 23. pii: 201708852. doi:, 10.1073/pnas.1708852114. PMID:29078335<ref>PMID:29078335</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6b27" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Petegem, F Van]]
 [[Category: Yuen, S M.Wong King]]

6b27

From Proteopedia

Revision as of 07:41, 8 November 2017

Crystal structure of human STAC2 Tandem SH3 Domains (296-411) in complex with a CaV1.1 II-III loop peptide

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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