4Q95

Crystal structure of HRASLS3/LRAT chimeric protein

Summary for 4Q95

• Entry DOI: 10.2210/pdb4q95/pdb
• Related: 4DOT
• Descriptor: HRAS-like suppressor 3, Lecithin retinol acyltransferase, HEPTANOIC ACID (3 entities in total)
• Functional Keywords: lecithin:retinol acyltransferase, alpha/beta fold, acylation, membrane, transferase
• Biological source: Homo sapiens (human, mouse); More
• Cellular location: Membrane ; Single-pass membrane protein : P53816
• Total number of polymer chains: 2
• Total formula weight: 34173.26

Authors

Golczak, M.,Kiser, P.D.,Sears, A.E.,Palczewski, K. (deposition date: 2014-04-29, release date: 2014-10-29, Last modification date: 2024-11-20)

Primary citation

Golczak, M.,Sears, A.E.,Kiser, P.D.,Palczewski, K.
LRAT-specific domain facilitates vitamin A metabolism by domain swapping in HRASLS3.
Nat.Chem.Biol., 11:26-32, 2015

PubMed Abstract: Cellular uptake of vitamin A, production of visual chromophore and triglyceride homeostasis in adipocytes depend on two representatives of the vertebrate N1pC/P60 protein family, lecithin:retinol acyltransferase (LRAT) and HRAS-like tumor suppressor 3 (HRASLS3). Both proteins function as lipid-metabolizing enzymes but differ in their substrate preferences and dominant catalytic activity. The mechanism of this catalytic diversity is not understood. Here, by using a gain-of-function approach, we identified a specific sequence responsible for the substrate specificity of N1pC/P60 proteins. A 2.2-Å crystal structure of the HRASLS3-LRAT chimeric enzyme in a thioester catalytic intermediate state revealed a major structural rearrangement accompanied by three-dimensional domain swapping dimerization not observed in native HRASLS proteins. Structural changes affecting the active site environment contributed to slower hydrolysis of the catalytic intermediate, supporting efficient acyl transfer. These findings reveal structural adaptation that facilitates selective catalysis and mechanism responsible for diverse substrate specificity within the LRAT-like enzyme family.

PubMed: 25383759
DOI: 10.1038/nchembio.1687

Experimental method

X-RAY DIFFRACTION (2.2 Å)