Differential Membrane Binding Mechanics of Synaptotagmin Isoforms Observed in Atomic Detail

Vermaas, Josh V.; Tajkhorshid, Emad

doi:10.1021/acs.biochem.6b00468

Title: Differential Membrane Binding Mechanics of Synaptotagmin Isoforms Observed in Atomic Detail

Journal Article · Mon Dec 05 00:00:00 EST 2016 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.6b00468· OSTI ID:1469837

Vermaas, Josh V. ^[1]; Tajkhorshid, Emad ^[2]

Univ. of Illinois at Urbana-Champaign, IL (United States). Center for Biophysics and Quantitative Biology, Dept. of Biochemistry, and Beckman Inst. for Advanced Science and Technology
Univ. of Illinois at Urbana-Champaign, IL (United States). Center for Biophysics and Quantitative Biology, Dept. of Biochemistry

Synaptotagmin (Syt) is a membrane-associated protein involved in vesicle fusion through the SNARE complex that is found throughout the human body in 17 different isoforms. These isoforms have two membrane-binding C2 domains, which sense Ca²⁺ and thereby promote anionic membrane binding and lead to vesicle fusion. Through molecular dynamics simulations using the highly mobile membrane mimetic acclerated bilayer model, we have investigated how small protein sequence changes in the Ca²⁺-binding loops of the C2 domains may give rise to the experimentally determined difference in binding kinetics between Syt-1 and Syt-7 isoforms. Syt-7 C2 domains are found to form more close contacts with anionic phospholipid headgroups, particularly in loop 1, where an additional positive charge in Syt-7 draws the loop closer to the membrane and causes the anchoring residue F167 to insert deeper into the bilayer than the corresponding methionine in Syt-1 (M173). By performing additional replica exchange umbrella sampling calculations, we demonstrate that these additional contacts increase the energetic cost of unbinding the Syt-7 C2 domains from the bilayer, causing them to unbind more slowly than their counterparts in Syt-1.

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Research Organization:: Univ. of Illinois at Urbana-Champaign, IL (United States). Beckman Inst. for Advanced Science and Technology; Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). National Energy Research Scientific Computing Center (NERSC)

Sponsoring Organization:: USDOE Office of Science (SC); USDOE National Nuclear Security Administration (NNSA)

Grant/Contract Number:: AC02-05CH11231; AC04-94AL85000; FG02-97ER25308

OSTI ID:: 1469837

Alternate ID(s):: OSTI ID: 1479669

Journal Information:: Biochemistry, Vol. 56, Issue 1; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 28 works

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