6GN5

CRYSTAL STRUCTURE OF HUMAN GRAMD1C START DOMAIN

Summary for 6GN5

• Entry DOI: 10.2210/pdb6gn5/pdb
• Descriptor: GRAM domain-containing protein 1C, (4S)-2-METHYL-2,4-PENTANEDIOL (3 entities in total)
• Functional Keywords: alpha/beta helix grip fold, sterol binding, lipid transport
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 23033.90

Authors

Friese, A.,Vetter, I.R. (deposition date: 2018-05-30, release date: 2019-06-19, Last modification date: 2024-11-06)

Primary citation

Laraia, L.,Friese, A.,Corkery, D.P.,Konstantinidis, G.,Erwin, N.,Hofer, W.,Karatas, H.,Klewer, L.,Brockmeyer, A.,Metz, M.,Scholermann, B.,Dwivedi, M.,Li, L.,Rios-Munoz, P.,Kohn, M.,Winter, R.,Vetter, I.R.,Ziegler, S.,Janning, P.,Wu, Y.W.,Waldmann, H.
The cholesterol transfer protein GRAMD1A regulates autophagosome biogenesis.
Nat.Chem.Biol., 15:710-720, 2019

PubMed Abstract: Autophagy mediates the degradation of damaged proteins, organelles and pathogens, and plays a key role in health and disease. Thus, the identification of new mechanisms involved in the regulation of autophagy is of major interest. In particular, little is known about the role of lipids and lipid-binding proteins in the early steps of autophagosome biogenesis. Using target-agnostic, high-content, image-based identification of indicative phenotypic changes induced by small molecules, we have identified autogramins as a new class of autophagy inhibitor. Autogramins selectively target the recently discovered cholesterol transfer protein GRAM domain-containing protein 1A (GRAMD1A, which had not previously been implicated in autophagy), and directly compete with cholesterol binding to the GRAMD1A StART domain. GRAMD1A accumulates at sites of autophagosome initiation, affects cholesterol distribution in response to starvation and is required for autophagosome biogenesis. These findings identify a new biological function of GRAMD1A and a new role for cholesterol in autophagy.

PubMed: 31222192
DOI: 10.1038/s41589-019-0307-5

Experimental method

X-RAY DIFFRACTION (1.41 Å)