Structure of the endocytic adaptor complex reveals the basis for efficient membrane anchoring during clathrin-mediated endocytosis

Javier Lizarrondo, David P. Klebl, Stephan Niebling, Marc Abella, Martin A. Schroer, Haydyn D. T. Mertens, Katharina Veith, Roland Thuenauer, Dmitri I. Svergun, Michal Skruzny, Frank Sobott, Stephen P. Muench and Maria M. Garcia-Alai ()
Additional contact information
Javier Lizarrondo: Hamburg Outstation
David P. Klebl: University of Leeds
Stephan Niebling: Hamburg Outstation
Marc Abella: Max Planck Institute for Terrestrial Microbiology and LOEWE Center for Synthetic Microbiology (SYNMIKRO)
Martin A. Schroer: Hamburg Outstation
Haydyn D. T. Mertens: Hamburg Outstation
Katharina Veith: Hamburg Outstation
Roland Thuenauer: Leibniz Institute for Experimental Virology
Dmitri I. Svergun: Hamburg Outstation
Michal Skruzny: Max Planck Institute for Terrestrial Microbiology and LOEWE Center for Synthetic Microbiology (SYNMIKRO)
Frank Sobott: University of Leeds
Stephen P. Muench: University of Leeds
Maria M. Garcia-Alai: Hamburg Outstation

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract During clathrin-mediated endocytosis, a complex and dynamic network of protein-membrane interactions cooperate to achieve membrane invagination. Throughout this process in yeast, endocytic coat adaptors, Sla2 and Ent1, must remain attached to the plasma membrane to transmit force from the actin cytoskeleton required for successful membrane invagination. Here, we present a cryo-EM structure of a 16-mer complex of the ANTH and ENTH membrane-binding domains from Sla2 and Ent1 bound to PIP2 that constitutes the anchor to the plasma membrane. Detailed in vitro and in vivo mutagenesis of the complex interfaces delineate the key interactions for complex formation and deficient cell growth phenotypes demonstrate its biological relevance. A hetero-tetrameric unit binds PIP2 molecules at the ANTH-ENTH interfaces and can form larger assemblies to contribute to membrane remodeling. Finally, a time-resolved small-angle X-ray scattering study of the interaction of these adaptor domains in vitro suggests that ANTH and ENTH domains have evolved to achieve a fast subsecond timescale assembly in the presence of PIP2 and do not require further proteins to form a stable complex. Together, these findings provide a molecular understanding of an essential piece in the molecular puzzle of clathrin-coated endocytic sites.

Date: 2021
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DOI: 10.1038/s41467-021-23151-7

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