6b27
From Proteopedia
Crystal structure of human STAC2 Tandem SH3 Domains (296-411) in complex with a CaV1.1 II-III loop peptide
Structural highlights
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 PubMedExcitation-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
| ||||||||||||||||||||
