The Dysferlin C2A Domain Binds PI(4,5)P2 and Penetrates Membranes.
C2 domain
CEST
calcium
dysferlin
genetic code expansion
Journal
Journal of molecular biology
ISSN: 1089-8638
Titre abrégé: J Mol Biol
Pays: Netherlands
ID NLM: 2985088R
Informations de publication
Date de publication:
01 09 2023
01 09 2023
Historique:
received:
06
02
2023
revised:
22
06
2023
accepted:
27
06
2023
pmc-release:
01
09
2024
medline:
15
8
2023
pubmed:
6
7
2023
entrez:
5
7
2023
Statut:
ppublish
Résumé
Dysferlin is a large membrane protein found most prominently in striated muscle. Loss of dysferlin activity is associated with reduced exocytosis, abnormal intracellular Ca2+ and the muscle diseases limb-girdle muscular dystrophy and Miyoshi myopathy. The cytosolic region of dysferlin consists of seven C2 domains with mutations in the C2A domain at the N-terminus resulting in pathology. Despite the importance of Ca2+ and membrane binding activities of the C2A domain for dysferlin function, the mechanism of the domain remains poorly characterized. In this study we find that the C2A domain preferentially binds membranes containing PI(4,5)P2 through an interaction mediated by residues Y23, K32, K33, and R77 on the concave face of the domain. We also found that subsequent to membrane binding, the C2A domain inserts residues on the Ca2+ binding loops into the membrane. Analysis of solution NMR measurements indicate that the domain inhabits two distinct structural states, with Ca2+ shifting the population between states towards a more rigid structure with greater affinity for PI(4,5)P2. Based on our results, we propose a mechanism where Ca
Identifiants
pubmed: 37406927
pii: S0022-2836(23)00292-9
doi: 10.1016/j.jmb.2023.168193
pmc: PMC10699586
mid: NIHMS1945470
pii:
doi:
Substances chimiques
Calcium
SY7Q814VUP
Calcium-Binding Proteins
0
Dysferlin
0
Membrane Proteins
0
Phosphatidylinositol 4,5-Diphosphate
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
168193Subventions
Organisme : NIDCD NIH HHS
ID : R01 DC014588
Pays : United States
Organisme : NIGMS NIH HHS
ID : RM1 GM144227
Pays : United States
Organisme : NIH HHS
ID : S10 OD018518
Pays : United States
Informations de copyright
Published by Elsevier Ltd.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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