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Munc13 structural transitions and oligomers that may choreograph successive stages in vesicle priming for neurotransmitter release.

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Grushin K, Kalyana Sundaram RV, Sindelar CV, Rothman JE
OpenAccess logo Proc Natl Acad Sci U S A 119 (2022)
Related entries: 7t7c, 7t7r, 7t7v, 7t7x

Cited: 18 times
EuropePMC logo PMID: 35135883

Abstract

How can exactly six SNARE complexes be assembled under each synaptic vesicle? Here we report cryo-EM crystal structures of the core domain of Munc13, the key chaperone that initiates SNAREpin assembly. The functional core of Munc13, consisting of C1-C2B-MUN-C2C (Munc13C) spontaneously crystallizes between phosphatidylserine-rich bilayers in two distinct conformations, each in a radically different oligomeric state. In the open conformation (state 1), Munc13C forms upright trimers that link the two bilayers, separating them by ∼21 nm. In the closed conformation, six copies of Munc13C interact to form a lateral hexamer elevated ∼14 nm above the bilayer. Open and closed conformations differ only by a rigid body rotation around a flexible hinge, which when performed cooperatively assembles Munc13 into a lateral hexamer (state 2) in which the key SNARE assembly-activating site of Munc13 is autoinhibited by its neighbor. We propose that each Munc13 in the lateral hexamer ultimately assembles a single SNAREpin, explaining how only and exactly six SNARE complexes are templated. We suggest that state 1 and state 2 may represent two successive states in the synaptic vesicle supply chain leading to "primed" ready-release vesicles in which SNAREpins are clamped and ready to release (state 3).

Reviews citing this publication (9)

  1. Vesicle trafficking and vesicle fusion: mechanisms, biological functions, and their implications for potential disease therapy. Cui L, Li H, Xi Y, Hu Q, Liu H, Fan J, Xiang Y, Zhang X, Shui W, Lai Y. Mol Biomed 3 29 (2022)
  2. Energetics, kinetics, and pathways of SNARE assembly in membrane fusion. Zhang Y, Ma L, Bao H. Crit Rev Biochem Mol Biol 57 443-460 (2022)
  3. Neuronal SNARE complex assembly guided by Munc18-1 and Munc13-1. Wang S, Ma C. FEBS Open Bio 12 1939-1957 (2022)
  4. UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target. Willemse SW, Harley P, van Eijk RPA, Demaegd KC, Zelina P, Pasterkamp RJ, van Damme P, Ingre C, van Rheenen W, Veldink JH, Kiernan MC, Al-Chalabi A, van den Berg LH, Fratta P, van Es MA. J Neurol Neurosurg Psychiatry 94 649-656 (2023)
  5. Complexin Membrane Interactions: Implications for Synapse Evolution and Function. Lottermoser JA, Dittman JS. J Mol Biol 435 167774 (2023)
  6. On the difficulties of characterizing weak protein interactions that are critical for neurotransmitter release. Rizo J, David G, Fealey ME, Jaczynska K. FEBS Open Bio 12 1912-1938 (2022)
  7. Mechanisms of SNARE proteins in membrane fusion. Jahn R, Cafiso DC, Tamm LK. Nat Rev Mol Cell Biol 25 101-118 (2024)
  8. The benefits of clustering in TNF receptor superfamily signaling. Vanamee ÉS, Faustman DL. Front Immunol 14 1225704 (2023)
  9. The machinery of vesicle fusion. Stanton AE, Hughson FM. Curr Opin Cell Biol 83 102191 (2023)

Articles citing this publication (9)

  1. All-atom molecular dynamics simulations of Synaptotagmin-SNARE-complexin complexes bridging a vesicle and a flat lipid bilayer. Rizo J, Sari L, Qi Y, Im W, Lin MM. Elife 11 e76356 (2022)
  2. Analysis of tripartite Synaptotagmin-1-SNARE-complexin-1 complexes in solution. Jaczynska K, Esquivies L, Pfuetzner RA, Alten B, Brewer KD, Zhou Q, Kavalali ET, Brunger AT, Rizo J. FEBS Open Bio 13 26-50 (2023)
  3. Munc13- and SNAP25-dependent molecular bridges play a key role in synaptic vesicle priming. Papantoniou C, Laugks U, Betzin J, Capitanio C, Ferrero JJ, Sánchez-Prieto J, Schoch S, Brose N, Baumeister W, Cooper BH, Imig C, Lučić V. Sci Adv 9 eadf6222 (2023)
  4. SNARE Proteins in Synaptic Vesicle Fusion. Palfreyman MT, West SE, Jorgensen EM. Adv Neurobiol 33 63-118 (2023)
  5. Roles for diacylglycerol in synaptic vesicle priming and release revealed by complete reconstitution of core protein machinery. Kalyana Sundaram RV, Chatterjee A, Bera M, Grushin K, Panda A, Li F, Coleman J, Lee S, Ramakrishnan S, Ernst AM, Gupta K, Rothman JE, Krishnakumar SS. Proc Natl Acad Sci U S A 120 e2309516120 (2023)
  6. Diacylglycerol-dependent hexamers of the SNARE-assembling chaperone Munc13-1 cooperatively bind vesicles. Li F, Grushin K, Coleman J, Pincet F, Rothman JE. Proc Natl Acad Sci U S A 120 e2306086120 (2023)
  7. Phorbolester-activated Munc13-1 and ubMunc13-2 exert opposing effects on dense-core vesicle secretion. Houy S, Martins JS, Lipstein N, Sørensen JB. Elife 11 e79433 (2022)
  8. Synaptophysin chaperones the assembly of 12 SNAREpins under each ready-release vesicle. Bera M, Radhakrishnan A, Coleman J, K Sundaram RV, Ramakrishnan S, Pincet F, Rothman JE. Proc Natl Acad Sci U S A 120 e2311484120 (2023)
  9. Visualizing Presynaptic Active Zones and Synaptic Vesicles. Heckmann M, Pauli M. Front Synaptic Neurosci 14 901341 (2022)


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