Architecture of the ESCPE-1 membrane coat

The research was first published online [June 15^th, 2023] in the journal Nature Structural & Molecular Biology

A common activity in our daily household chores is separating paper, glass, cans, and plastic to deposit them in the appropriate containers. Through recycling, we can reduce resource consumption, save energy, and minimize waste. Similarly, our cells recycle many of their components to achieve the same benefits.

In the realm of cellular biology, the recycling of membrane proteins plays a vital role in maintaining cellular function and equilibrium. A remarkable protein complex called endosomal sorting complex for promoting exit 1 (ESCPE-1) has emerged as a key player in this process. By rescuing transmembrane proteins from the endolysosomal pathway, ESCPE-1 ensures their safe transport to the trans-Golgi network and ultimately to the plasma membrane. While the importance of ESCPE-1 in recycling is well-established, the underlying mechanisms governing its function have remained elusive. Recent ground-breaking research has started to shed light on the intricate workings of ESCPE-1 and its role in tubule-based endosomal sorting.

A multidisciplinary research team coordinated by Aitor Hierro, Ikerbasque lead researcher at CIC bioGUNE, Biofisika Institute, NIH (National Institutes of Health, USA), BSC (Barcelona Supercomputing Center), and ICVV (Institute of Vine and Wine Sciences) has revealed the structure of ESCPE-1 (Endosomal Sorting Complex Promoting Exit 1), which is responsible for transporting and reusing over 60 different proteins. This research provides valuable insights into the intricate mechanisms of tubular-based cargo sorting mediated by ESCPE-1. By elucidating the relationships between membrane interactions, cargo recognition, and coat formation, the study enhances our understanding of membrane protein recycling and its role in cellular processes.

"Many of the proteins transported and reused by this cellular machinery for protein recycling are cell receptors involved in cell growth and proliferation, and they appear dysregulated in different types of cancer. In this study, we have revealed the organization of ESCPE-1 at the atomic level and how the receptors to be recycled contribute to their own transport. Going back to the analogy of paper, glass, cans, and plastic, it is like discovering the mechanism of selective collection for one of these containers," explains Aitor Hierro.

The work, which has been carried out over the past five years, has utilized two of the most relevant techniques in structural biology: X-ray crystallography and cryo-electron microscopy. Both techniques require large infrastructures like those found at CIC bioGUNE and BREM (Basque Resource for Electron Microscopy) at the Biofisika Institute, which together have successfully addressed this study.

FUNDING:

Many institutions participated in the study, including CIC bioGUNE, Biofisika Institute, NIH (National Institutes of Health, USA), BSC (Barcelona Supercomputing Center), and ICVV (Institute of Vine and Wine Sciences). This work was supported by the Spanish Ministry of Economy and Competitiveness Grant BFU2017-88766-R, The Ministry of Science and Innovation Grant PID2020-119132GB-I00 (to A.H.), the Intramural Program of NICHD, NIH (ZIA HD001607 to J.S.B.), the Swiss National Science Foundation (SNF) grant 205321 179041 (to DCD), the Human Frontiers Science Program (HFSP) grant RGP0017/2020 (to DCD) and the PID2021-127309NB-I00 funded by AEI/10.13039/501100011033/ FEDER, UE (to DCD). This study made use of the Diamond Light Source (Oxfordshire, UK) proposal MX20113, ALBA synchrotron beamline BL13-XALOC, the cryo-EM facilities at the UK national Electron Bio-imaging Centre (eBIC), proposals EM17171-6 and EM17171, and The Midlands Regional Cryo-EM Facility at the Leicester Institute of Structural and Chemical Biology (LISCB). We thank Christos Savva (LISCB, University of Leicester) for his help in cryo-EM data collection.

Publication

Lopez-Robles et al. Architecture of the ESCPE-1 membrane coat. Nature Structural & Molecular Biology June 15^th, DOI: 10.1038/s41594-023-01014-7

About CIC bioGUNE

The Centre for Cooperative Research in Biosciences (CIC bioGUNE), member of the Basque Research & Technology Alliance (BRTA), located in the Bizkaia Technology Park, is a biomedical research organisation conducting cutting-edge research at the interface between structural, molecular and cell biology, with a particular focus on generating knowledge on the molecular bases of disease, for use in the development of new diagnostic methods and advanced therapies.

About Ikerbasque

Ikerbasque - Basque Foundation for Science - is the result of an initiative of the Department of Education of the Basque Government that aims to reinforce the commitment to scientific research by attracting, recovering and consolidating excellent researchers from all over the world. Currently, it is a consolidated organization that has 290 researchers/s, who develop their work in all fields of knowledge.