Structural Basis for the Acyltransferase Activity of Lecithin: Retinol Acyltransferase-like Proteins
Abstract
Lecithin:retinol acyltransferase-like proteins, also referred to as HRAS-like tumor suppressors, comprise a vertebrate subfamily of papain-like or NlpC/P60 thiol proteases that function as phospholipid-metabolizing enzymes. HRAS-like tumor suppressor 3, a representative member of this group, plays a key role in regulating triglyceride accumulation and energy expenditure in adipocytes and therefore constitutes a novel pharmacological target for treatment of metabolic disorders causing obesity. Here, we delineate a catalytic mechanism common to lecithin:retinol acyltransferase-like proteins and provide evidence for their alternative robust lipid-dependent acyltransferase enzymatic activity. We also determined high resolution crystal structures of HRAS-like tumor suppressor 2 and 3 to gain insight into their active site architecture. Based on this structural analysis, two conformational states of the catalytic Cys-113 were identified that differ in reactivity and thus could define the catalytic properties of these two proteins. Finally, these structures provide a model for the topology of these enzymes and allow identification of the protein-lipid bilayer interface. This study contributes to the enzymatic and structural understanding of HRAS-like tumor suppressor enzymes.
- Authors:
-
- Case Western
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- National Institutes of Health (NIH)
- OSTI Identifier:
- 1048570
- Resource Type:
- Journal Article
- Journal Name:
- J. Biol. Chem.
- Additional Journal Information:
- Journal Volume: 287; Journal Issue: (28) ; 07, 2012; Journal ID: ISSN 0021-9258
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ARCHITECTURE; BIOLOGY; CATALYSIS; CRYSTAL STRUCTURE; ENZYMES; EXPENDITURES; LECITHINS; LIPASES; LIPIDS; METABOLIC DISEASES; NEOPLASMS; PROTEINS; RESOLUTION; TARGETS; THIOLS; TOPOLOGY; TRIGLYCERIDES; VERTEBRATES
Citation Formats
Golczak, Marcin, Kiser, Philip D, Sears, Avery E, Lodowski, David T, Blaner, William S, Palczewski, Krzysztof, and Columbia). Structural Basis for the Acyltransferase Activity of Lecithin: Retinol Acyltransferase-like Proteins. United States: N. p., 2012.
Web. doi:10.1074/jbc.M112.361550.
Golczak, Marcin, Kiser, Philip D, Sears, Avery E, Lodowski, David T, Blaner, William S, Palczewski, Krzysztof, & Columbia). Structural Basis for the Acyltransferase Activity of Lecithin: Retinol Acyltransferase-like Proteins. United States. https://doi.org/10.1074/jbc.M112.361550
Golczak, Marcin, Kiser, Philip D, Sears, Avery E, Lodowski, David T, Blaner, William S, Palczewski, Krzysztof, and Columbia). 2012.
"Structural Basis for the Acyltransferase Activity of Lecithin: Retinol Acyltransferase-like Proteins". United States. https://doi.org/10.1074/jbc.M112.361550.
@article{osti_1048570,
title = {Structural Basis for the Acyltransferase Activity of Lecithin: Retinol Acyltransferase-like Proteins},
author = {Golczak, Marcin and Kiser, Philip D and Sears, Avery E and Lodowski, David T and Blaner, William S and Palczewski, Krzysztof and Columbia)},
abstractNote = {Lecithin:retinol acyltransferase-like proteins, also referred to as HRAS-like tumor suppressors, comprise a vertebrate subfamily of papain-like or NlpC/P60 thiol proteases that function as phospholipid-metabolizing enzymes. HRAS-like tumor suppressor 3, a representative member of this group, plays a key role in regulating triglyceride accumulation and energy expenditure in adipocytes and therefore constitutes a novel pharmacological target for treatment of metabolic disorders causing obesity. Here, we delineate a catalytic mechanism common to lecithin:retinol acyltransferase-like proteins and provide evidence for their alternative robust lipid-dependent acyltransferase enzymatic activity. We also determined high resolution crystal structures of HRAS-like tumor suppressor 2 and 3 to gain insight into their active site architecture. Based on this structural analysis, two conformational states of the catalytic Cys-113 were identified that differ in reactivity and thus could define the catalytic properties of these two proteins. Finally, these structures provide a model for the topology of these enzymes and allow identification of the protein-lipid bilayer interface. This study contributes to the enzymatic and structural understanding of HRAS-like tumor suppressor enzymes.},
doi = {10.1074/jbc.M112.361550},
url = {https://www.osti.gov/biblio/1048570},
journal = {J. Biol. Chem.},
issn = {0021-9258},
number = (28) ; 07, 2012,
volume = 287,
place = {United States},
year = {Wed Oct 10 00:00:00 EDT 2012},
month = {Wed Oct 10 00:00:00 EDT 2012}
}