Autoinhibition of Endophilin in Solution Via Interdomain Interactions

Overview

Journal Biophys J

Publisher Cell Press

Specialty Biophysics

Date 2013 Feb 28

PMID 23442861

Citations 15

Authors

Francisco X Vazquez

Vinzenz M Unger

Gregory A Voth

Affiliations

Soon will be listed here.

Abstract

Endophilin is a key protein involved in clathrin-mediated endocytosis. Previous computational and experimental work suggested that the N-terminal helix is embedded into the membrane to induce curvature; however, the role of the SH3 domain remains controversial. To address this issue, we performed computer simulations of the endophilin dimer in solution to understand the interaction between the N-BAR and SH3 domains and its effect on biological function. We predict that the helix binds to the SH3 domain through hydrophobic and salt-bridge interactions. This protects the hydrophobic residues on both domains and keeps the SH3 domain near the end of the N-BAR domain, in agreement with previous experimental results. The complex has a binding strength similar to a few hydrogen bonds (13.0 ± 0.6 kcal/mol), and the SH3 domain stabilizes the structure of the N-terminal helix in solution. Electrostatic calculations show a large region of strongly positive electrostatic potential near the N-terminal that can orient the helix toward the membrane and likely embed the helix into the membrane surface. This predicted mechanism suggests that endophilin can select for both curvature and electrostatic potential when interacting with membranes, highlighting the importance of the SH3 domain in regulating the function of endophilin.

Citing Articles

Biology of endophilin and it's role in disease.

Yang L, Huang A, Xu W Front Immunol. 2023; 14:1297506.

PMID: 38116012 PMC: 10728279. DOI: 10.3389/fimmu.2023.1297506.

GTP-stimulated membrane fission by the N-BAR protein AMPH-1.

Kustigian L, Gong X, Gai W, Thongchol J, Zhang J, Puchalla J Traffic. 2022; 24(1):34-47.

PMID: 36435193 PMC: 9825645. DOI: 10.1111/tra.12875.

The endophilin curvature-sensitive motif requires electrostatic guidance to recycle synaptic vesicles in vivo.

Zhang L, Wang Y, Dong Y, Pant A, Liu Y, Masserman L Dev Cell. 2022; 57(6):750-766.e5.

PMID: 35303431 PMC: 8969179. DOI: 10.1016/j.devcel.2022.02.021.

Unfolding Mechanisms and Conformational Stability of the Dimeric Endophilin N-BAR Domain.

Jin R, Grasso M, Zhou M, Marmorstein R, Baumgart T ACS Omega. 2021; 6(32):20790-20803.

PMID: 34423187 PMC: 8374900. DOI: 10.1021/acsomega.1c01905.

Molecular Regulation of the RhoGAP GRAF3 and Its Capacity to Limit Blood Pressure In Vivo.

Dee R, Bai X, Mack C, Taylor J Cells. 2020; 9(4).

PMID: 32331391 PMC: 7226614. DOI: 10.3390/cells9041042.

References

Schmidt A, Wolde M, Thiele C, Fest W, Kratzin H, Podtelejnikov A . Endophilin I mediates synaptic vesicle formation by transfer of arachidonate to lysophosphatidic acid. Nature. 1999; 401(6749):133-41. DOI: 10.1038/43613. View

Mayer B . SH3 domains: complexity in moderation. J Cell Sci. 2001; 114(Pt 7):1253-63. DOI: 10.1242/jcs.114.7.1253. View

Raiteri P, Laio A, Gervasio F, Micheletti C, Parrinello M . Efficient reconstruction of complex free energy landscapes by multiple walkers metadynamics. J Phys Chem B. 2006; 110(8):3533-9. DOI: 10.1021/jp054359r. View

Bhatia V, Madsen K, Bolinger P, Kunding A, Hedegard P, Gether U . Amphipathic motifs in BAR domains are essential for membrane curvature sensing. EMBO J. 2009; 28(21):3303-14. PMC: 2776096. DOI: 10.1038/emboj.2009.261. View

Masuda M, Takeda S, Sone M, Ohki T, Mori H, Kamioka Y . Endophilin BAR domain drives membrane curvature by two newly identified structure-based mechanisms. EMBO J. 2006; 25(12):2889-97. PMC: 1500852. DOI: 10.1038/sj.emboj.7601176. View

Phillips J, Braun R, Wang W, Gumbart J, Tajkhorshid E, Villa E . Scalable molecular dynamics with NAMD. J Comput Chem. 2005; 26(16):1781-802. PMC: 2486339. DOI: 10.1002/jcc.20289. View

Gallop J, Jao C, Kent H, Butler P, Evans P, Langen R . Mechanism of endophilin N-BAR domain-mediated membrane curvature. EMBO J. 2006; 25(12):2898-910. PMC: 1500843. DOI: 10.1038/sj.emboj.7601174. View

Wang Q, Kaan H, Hooda R, Goh S, Sondermann H . Structure and plasticity of Endophilin and Sorting Nexin 9. Structure. 2008; 16(10):1574-87. DOI: 10.1016/j.str.2008.07.016. View

Laio A, Parrinello M . Escaping free-energy minima. Proc Natl Acad Sci U S A. 2002; 99(20):12562-6. PMC: 130499. DOI: 10.1073/pnas.202427399. View

10.

Trempe J, Chen C, Grenier K, Camacho E, Kozlov G, McPherson P . SH3 domains from a subset of BAR proteins define a Ubl-binding domain and implicate parkin in synaptic ubiquitination. Mol Cell. 2010; 36(6):1034-47. DOI: 10.1016/j.molcel.2009.11.021. View

11.

Barducci A, Bussi G, Parrinello M . Well-tempered metadynamics: a smoothly converging and tunable free-energy method. Phys Rev Lett. 2008; 100(2):020603. DOI: 10.1103/PhysRevLett.100.020603. View

12.

Rao Y, Ma Q, Vahedi-Faridi A, Sundborger A, Pechstein A, Puchkov D . Molecular basis for SH3 domain regulation of F-BAR-mediated membrane deformation. Proc Natl Acad Sci U S A. 2010; 107(18):8213-8. PMC: 2889545. DOI: 10.1073/pnas.1003478107. View

13.

McMahon H, Gallop J . Membrane curvature and mechanisms of dynamic cell membrane remodelling. Nature. 2005; 438(7068):590-6. DOI: 10.1038/nature04396. View

14.

Gortat A, San-Roman M, Vannier C, Schmidt A . Single point mutation in Bin/Amphiphysin/Rvs (BAR) sequence of endophilin impairs dimerization, membrane shaping, and Src homology 3 domain-mediated partnership. J Biol Chem. 2011; 287(6):4232-47. PMC: 3281743. DOI: 10.1074/jbc.M111.325837. View

15.

Humphrey W, Dalke A, Schulten K . VMD: visual molecular dynamics. J Mol Graph. 1996; 14(1):33-8, 27-8. DOI: 10.1016/0263-7855(96)00018-5. View

16.

MacKerell Jr A, Feig M, Brooks 3rd C . Extending the treatment of backbone energetics in protein force fields: limitations of gas-phase quantum mechanics in reproducing protein conformational distributions in molecular dynamics simulations. J Comput Chem. 2004; 25(11):1400-15. DOI: 10.1002/jcc.20065. View

17.

Ringstad N, Gad H, Low P, Di Paolo G, Brodin L, Shupliakov O . Endophilin/SH3p4 is required for the transition from early to late stages in clathrin-mediated synaptic vesicle endocytosis. Neuron. 2000; 24(1):143-54. DOI: 10.1016/s0896-6273(00)80828-4. View

18.

Mim C, Cui H, Gawronski-Salerno J, Frost A, Lyman E, Voth G . Structural basis of membrane bending by the N-BAR protein endophilin. Cell. 2012; 149(1):137-45. PMC: 3319357. DOI: 10.1016/j.cell.2012.01.048. View

19.

MacKerell A, Bashford D, Bellott M, Dunbrack R, Evanseck J, Field M . All-atom empirical potential for molecular modeling and dynamics studies of proteins. J Phys Chem B. 2014; 102(18):3586-616. DOI: 10.1021/jp973084f. View

20.

Bai J, Hu Z, Dittman J, Pym E, Kaplan J . Endophilin functions as a membrane-bending molecule and is delivered to endocytic zones by exocytosis. Cell. 2010; 143(3):430-41. PMC: 2996235. DOI: 10.1016/j.cell.2010.09.024. View