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Exceptionally tight membrane-binding may explain the key role of the synaptotagmin-7 C 2 A domain in asynchronous neurotransmitter release.

التفاصيل البيبلوغرافية
العنوان: Exceptionally tight membrane-binding may explain the key role of the synaptotagmin-7 C 2 A domain in asynchronous neurotransmitter release.
المؤلفون: Voleti R; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390.; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390., Tomchick DR; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390.; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390., Südhof TC; Department of Molecular and Cellular Physiology, Stanford University Medical School, Stanford, CA 94305; tcs1@stanford.edu jose.rizo-rey@UTSouthwestern.edu.; Howard Hughes Medical Institute, Stanford University Medical School, Stanford, CA 94305., Rizo J; Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390; tcs1@stanford.edu jose.rizo-rey@UTSouthwestern.edu.; Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390.; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
المصدر: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2017 Oct 03; Vol. 114 (40), pp. E8518-E8527. Date of Electronic Publication: 2017 Sep 18.
نوع المنشور: 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.
اللغة: English
بيانات الدورية: Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Washington, DC : National Academy of Sciences
مواضيع طبية MeSH: Calcium/*metabolism , Cell Membrane/*metabolism , Neurotransmitter Agents/*metabolism , Synaptotagmin I/*metabolism , Synaptotagmins/*metabolism, Animals ; Crystallography, X-Ray ; Liposomes ; Protein Binding ; Protein Domains ; Rats ; Synaptic Transmission ; Synaptotagmin I/chemistry ; Synaptotagmin I/genetics ; Synaptotagmins/chemistry ; Synaptotagmins/genetics
مستخلص: Synaptotagmins (Syts) act as Ca 2+ sensors in neurotransmitter release by virtue of Ca 2+ -binding to their two C 2 domains, but their mechanisms of action remain unclear. Puzzlingly, Ca 2+ -binding to the C 2 B domain appears to dominate Syt1 function in synchronous release, whereas Ca 2+ -binding to the C 2 A domain mediates Syt7 function in asynchronous release. Here we show that crystal structures of the Syt7 C 2 A domain and C 2 AB region, and analyses of intrinsic Ca 2+ -binding to the Syt7 C2 domains using isothermal titration calorimetry, did not reveal major differences that could explain functional differentiation between Syt7 and Syt1. However, using liposome titrations under Ca 2+ saturating conditions, we show that the Syt7 C 2 A domain has a very high membrane affinity and dominates phospholipid binding to Syt7 in the presence or absence of l-α-phosphatidylinositol 4,5-diphosphate (PIP 2 ). For Syt1, the two Ca 2+ -saturated C 2 domains have similar affinities for membranes lacking PIP 2 , but the C 2 B domain dominates binding to PIP 2 -containing membranes. Mutagenesis revealed that the dramatic differences in membrane affinity between the Syt1 and Syt7 C 2 A domains arise in part from apparently conservative residue substitutions, showing how striking biochemical and functional differences can result from the cumulative effects of subtle residue substitutions. Viewed together, our results suggest that membrane affinity may be a key determinant of the functions of Syt C 2 domains in neurotransmitter release.
Competing Interests: The authors declare no conflict of interest.
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معلومات مُعتمدة: R35 NS097333 United States NS NINDS NIH HHS; S10 OD018027 United States OD NIH HHS; United States HHMI Howard Hughes Medical Institute; R01 NS037200 United States NS NINDS NIH HHS; R01 NS040944 United States NS NINDS NIH HHS; S10 RR026461 United States RR NCRR NIH HHS
فهرسة مساهمة: Keywords: X-ray crystallography; membrane binding; neurotransmitter release; synaptotagmin-1; synaptotagmin-7
سلسلة جزيئية: PDB 6ANJ; 6ANK
المشرفين على المادة: 0 (Liposomes)
0 (Neurotransmitter Agents)
0 (Synaptotagmin I)
0 (Syt1 protein, rat)
0 (Syt7 protein, rat)
134193-27-4 (Synaptotagmins)
SY7Q814VUP (Calcium)
تواريخ الأحداث: Date Created: 20170920 Date Completed: 20180626 Latest Revision: 20181113
رمز التحديث: 20231215
مُعرف محوري في PubMed: PMC5635908
DOI: 10.1073/pnas.1710708114
PMID: 28923929
قاعدة البيانات: MEDLINE
الوصف
تدمد:1091-6490
DOI:10.1073/pnas.1710708114