The middle lipin domain adopts a membrane-binding dimeric protein fold
| Autor: | Nimi M. Patel, Huan Wang, Reece M. Hoffmann, Jong Won Yang, Shujuan Gao, Karen Reue, Weijing Gu, Yong Mi Choi, Kaelin D. Fleming, John E. Burke, Michael V. Airola |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Models
Molecular Protein Folding Transcription Genetic General Physics and Astronomy Sequence Homology Crystallography X-Ray chemistry.chemical_compound Mice Models Membrane proteins Membrane lipids Conserved Sequence Sequence Deletion chemistry.chemical_classification Multidisciplinary Crystallography Adipogenesis Phosphatidic acid Recombinant Proteins Cell biology Amino Acid Membrane Transcription Protein Binding Science 1.1 Normal biological development and functioning Phosphatase Phosphatidate Phosphatase Hydrogen Deuterium Exchange-Mass Spectrometry Molecular Dynamics Simulation Article General Biochemistry Genetics and Molecular Biology Genetic Protein Domains Underpinning research 3T3-L1 Cells Animals Humans Amino Acid Sequence X-ray crystallography Mass spectrometry Sequence Homology Amino Acid Cell Membrane Membrane Proteins Molecular General Chemistry Subcellular localization Enzyme HEK293 Cells chemistry Membrane protein X-Ray Hydrogen–deuterium exchange Generic health relevance Protein Multimerization |
| Zdroj: | Nature communications, vol 12, iss 1 Nature Communications, Vol 12, Iss 1, Pp 1-14 (2021) Nature Communications |
| Popis: | Phospholipid synthesis and fat storage as triglycerides are regulated by lipin phosphatidic acid phosphatases (PAPs), whose enzymatic PAP function requires association with cellular membranes. Using hydrogen deuterium exchange mass spectrometry, we find mouse lipin 1 binds membranes through an N-terminal amphipathic helix, the Ig-like domain and HAD phosphatase catalytic core, and a middle lipin (M-Lip) domain that is conserved in mammalian and mammalian-like lipins. Crystal structures of the M-Lip domain reveal a previously unrecognized protein fold that dimerizes. The isolated M-Lip domain binds membranes both in vitro and in cells through conserved basic and hydrophobic residues. Deletion of the M-Lip domain in lipin 1 reduces PAP activity, membrane association, and oligomerization, alters subcellular localization, diminishes acceleration of adipocyte differentiation, but does not affect transcriptional co-activation. This establishes the M-Lip domain as a dimeric protein fold that binds membranes and is critical for full functionality of mammalian lipins. Lipins need to bind cell membranes before they can function as phosphatidic acid phosphatases. Here, the authors elucidate the structural basis of lipin membrane-association and identify a lipin domain with a novel protein fold that is critical for membrane binding and full functionality of lipins. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|