Faculty Collaboration Database

A kink in DWORF helical structure controls the activation of the sarcoplasmic reticulum Ca²⁺-ATPase. Structure 2022 Mar 03;30(3):360-370.e6

Date

12/08/2021

Pubmed ID

34875216

Pubmed Central ID

PMC8897251

DOI

10.1016/j.str.2021.11.003

Scopus ID

2-s2.0-85123018206 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

SERCA is a P-type ATPase embedded in the sarcoplasmic reticulum and plays a central role in muscle relaxation. SERCA's function is regulated by single-pass membrane proteins called regulins. Unlike other regulins, dwarf open reading frame (DWORF) expressed in cardiac muscle has a unique activating effect. Here, we determine the structure and topology of DWORF in lipid bilayers using a combination of oriented sample solid-state NMR spectroscopy and replica-averaged orientationally restrained molecular dynamics. We found that DWORF's structural topology consists of a dynamic N-terminal domain, an amphipathic juxtamembrane helix that crosses the lipid groups at an angle of 64°, and a transmembrane C-terminal helix with an angle of 32°. A kink induced by Pro15, unique to DWORF, separates the two helical domains. A single Pro15Ala mutant significantly decreases the kink and eliminates DWORF's activating effect on SERCA. Overall, our findings directly link DWORF's structural topology to its activating effect on SERCA.

Author List

Reddy UV, Weber DK, Wang S, Larsen EK, Gopinath T, De Simone A, Robia S, Veglia G

Author

Gopinath Tata PhD Assistant Professor in the Biophysics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Calcium-Binding Proteins
Lipid Bilayers
Molecular Dynamics Simulation
Sarcoplasmic Reticulum
Sarcoplasmic Reticulum Calcium-Transporting ATPases