Angiopoietin-like protein 4 inhibition of lipoprotein lipase: evidence for reversible complex formation
Elevated triglycerides are associated with an increased risk of cardiovascular disease, and lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglycerides from circulating lipoproteins. The N-terminal domain of angiopoietin-like protein 4 (ANGPTL4) inhibits LPL activity. AN...
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| Veröffentlicht in: | The Journal of biological chemistry 2013-10, Vol.288 (40), p.28524-28534 |
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| container_title | The Journal of biological chemistry |
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| creator | Lafferty, Michael J Bradford, Kira C Erie, Dorothy A Neher, Saskia B |
| description | Elevated triglycerides are associated with an increased risk of cardiovascular disease, and lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglycerides from circulating lipoproteins. The N-terminal domain of angiopoietin-like protein 4 (ANGPTL4) inhibits LPL activity. ANGPTL4 was previously described as an unfolding molecular chaperone of LPL that catalytically converts active LPL dimers into inactive monomers. Our studies show that ANGPTL4 is more accurately described as a reversible, noncompetitive inhibitor of LPL. We find that inhibited LPL is in a complex with ANGPTL4, and upon dissociation, LPL regains lipase activity. Furthermore, we have generated a variant of ANGPTL4 that is dependent on divalent cations for its ability to inhibit LPL. We show that LPL inactivation by this regulatable variant of ANGPTL4 is fully reversible after treatment with a chelator. |
| doi_str_mv | 10.1074/jbc.M113.497602 |
| format | Article |
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The N-terminal domain of angiopoietin-like protein 4 (ANGPTL4) inhibits LPL activity. ANGPTL4 was previously described as an unfolding molecular chaperone of LPL that catalytically converts active LPL dimers into inactive monomers. Our studies show that ANGPTL4 is more accurately described as a reversible, noncompetitive inhibitor of LPL. We find that inhibited LPL is in a complex with ANGPTL4, and upon dissociation, LPL regains lipase activity. Furthermore, we have generated a variant of ANGPTL4 that is dependent on divalent cations for its ability to inhibit LPL. We show that LPL inactivation by this regulatable variant of ANGPTL4 is fully reversible after treatment with a chelator.</description><identifier>ISSN: 0021-9258</identifier><identifier>EISSN: 1083-351X</identifier><identifier>DOI: 10.1074/jbc.M113.497602</identifier><identifier>PMID: 23960078</identifier><language>eng</language><publisher>United States: American Society for Biochemistry and Molecular Biology</publisher><subject>Angiopoietins - isolation & purification ; Angiopoietins - metabolism ; Animals ; Biocatalysis ; Cattle ; Chromatography, Affinity ; Cross-Linking Reagents ; Enzyme Activation ; Heparin ; Hot Temperature ; Lipids ; Lipoprotein Lipase - antagonists & inhibitors ; Lipoprotein Lipase - isolation & purification ; Lipoprotein Lipase - metabolism ; Microscopy, Atomic Force ; Models, Biological ; Multiprotein Complexes - metabolism ; Sepharose ; Time Factors</subject><ispartof>The Journal of biological chemistry, 2013-10, Vol.288 (40), p.28524-28534</ispartof><rights>2013 by The American Society for Biochemistry and Molecular Biology, Inc. 2013</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789953/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789953/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23960078$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lafferty, Michael J</creatorcontrib><creatorcontrib>Bradford, Kira C</creatorcontrib><creatorcontrib>Erie, Dorothy A</creatorcontrib><creatorcontrib>Neher, Saskia B</creatorcontrib><title>Angiopoietin-like protein 4 inhibition of lipoprotein lipase: evidence for reversible complex formation</title><title>The Journal of biological chemistry</title><addtitle>J Biol Chem</addtitle><description>Elevated triglycerides are associated with an increased risk of cardiovascular disease, and lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglycerides from circulating lipoproteins. The N-terminal domain of angiopoietin-like protein 4 (ANGPTL4) inhibits LPL activity. ANGPTL4 was previously described as an unfolding molecular chaperone of LPL that catalytically converts active LPL dimers into inactive monomers. Our studies show that ANGPTL4 is more accurately described as a reversible, noncompetitive inhibitor of LPL. We find that inhibited LPL is in a complex with ANGPTL4, and upon dissociation, LPL regains lipase activity. Furthermore, we have generated a variant of ANGPTL4 that is dependent on divalent cations for its ability to inhibit LPL. We show that LPL inactivation by this regulatable variant of ANGPTL4 is fully reversible after treatment with a chelator.</description><subject>Angiopoietins - isolation & purification</subject><subject>Angiopoietins - metabolism</subject><subject>Animals</subject><subject>Biocatalysis</subject><subject>Cattle</subject><subject>Chromatography, Affinity</subject><subject>Cross-Linking Reagents</subject><subject>Enzyme Activation</subject><subject>Heparin</subject><subject>Hot Temperature</subject><subject>Lipids</subject><subject>Lipoprotein Lipase - antagonists & inhibitors</subject><subject>Lipoprotein Lipase - isolation & purification</subject><subject>Lipoprotein Lipase - metabolism</subject><subject>Microscopy, Atomic Force</subject><subject>Models, Biological</subject><subject>Multiprotein Complexes - metabolism</subject><subject>Sepharose</subject><subject>Time Factors</subject><issn>0021-9258</issn><issn>1083-351X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkL1PwzAQxS0EoqUwsyGPLCn-SuwwIFUVX1IRC0hske1eWpfEDnFawX9PKloEt9zpvdPv6Q6hc0rGlEhxtTJ2_EQpH4tcZoQdoCEliic8pW-HaEgIo0nOUjVAJzGuSF8ip8dowHieESLVEC0mfuFCExx0zieVewfctKED57HAzi-dcZ0LHocSV64Je6-fdYRrDBs3B28Bl6HFLWygjc5UgG2omwo-t3Ktt4BTdFTqKsLZro_Q693ty_QhmT3fP04ns6RhWdYlgkBKcyuU1IbmhqjMZNxQq5VhmnEhS1YqUqaGKSsEVf3VZs5SIuWcZ5nlfIRufrjN2tQwt-C7VldF07pat19F0K7473i3LBZhU3Cp8jzdAi53gDZ8rCF2Re2iharSHsI6FlQIzlUqhexXL_5m_Ybsv8u_AY3afyg</recordid><startdate>20131004</startdate><enddate>20131004</enddate><creator>Lafferty, Michael J</creator><creator>Bradford, Kira C</creator><creator>Erie, Dorothy A</creator><creator>Neher, Saskia B</creator><general>American Society for Biochemistry and Molecular Biology</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20131004</creationdate><title>Angiopoietin-like protein 4 inhibition of lipoprotein lipase: evidence for reversible complex formation</title><author>Lafferty, Michael J ; Bradford, Kira C ; Erie, Dorothy A ; Neher, Saskia B</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p266t-40e519c487ab19b086b63b1ca8b2a2347f2f80f5b28c4418976bd25077d366c33</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Angiopoietins - isolation & purification</topic><topic>Angiopoietins - metabolism</topic><topic>Animals</topic><topic>Biocatalysis</topic><topic>Cattle</topic><topic>Chromatography, Affinity</topic><topic>Cross-Linking Reagents</topic><topic>Enzyme Activation</topic><topic>Heparin</topic><topic>Hot Temperature</topic><topic>Lipids</topic><topic>Lipoprotein Lipase - antagonists & inhibitors</topic><topic>Lipoprotein Lipase - isolation & purification</topic><topic>Lipoprotein Lipase - metabolism</topic><topic>Microscopy, Atomic Force</topic><topic>Models, Biological</topic><topic>Multiprotein Complexes - metabolism</topic><topic>Sepharose</topic><topic>Time Factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lafferty, Michael J</creatorcontrib><creatorcontrib>Bradford, Kira C</creatorcontrib><creatorcontrib>Erie, Dorothy A</creatorcontrib><creatorcontrib>Neher, Saskia B</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of biological chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lafferty, Michael J</au><au>Bradford, Kira C</au><au>Erie, Dorothy A</au><au>Neher, Saskia B</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Angiopoietin-like protein 4 inhibition of lipoprotein lipase: evidence for reversible complex formation</atitle><jtitle>The Journal of biological chemistry</jtitle><addtitle>J Biol Chem</addtitle><date>2013-10-04</date><risdate>2013</risdate><volume>288</volume><issue>40</issue><spage>28524</spage><epage>28534</epage><pages>28524-28534</pages><issn>0021-9258</issn><eissn>1083-351X</eissn><abstract>Elevated triglycerides are associated with an increased risk of cardiovascular disease, and lipoprotein lipase (LPL) is the rate-limiting enzyme for the hydrolysis of triglycerides from circulating lipoproteins. The N-terminal domain of angiopoietin-like protein 4 (ANGPTL4) inhibits LPL activity. ANGPTL4 was previously described as an unfolding molecular chaperone of LPL that catalytically converts active LPL dimers into inactive monomers. Our studies show that ANGPTL4 is more accurately described as a reversible, noncompetitive inhibitor of LPL. We find that inhibited LPL is in a complex with ANGPTL4, and upon dissociation, LPL regains lipase activity. Furthermore, we have generated a variant of ANGPTL4 that is dependent on divalent cations for its ability to inhibit LPL. We show that LPL inactivation by this regulatable variant of ANGPTL4 is fully reversible after treatment with a chelator.</abstract><cop>United States</cop><pub>American Society for Biochemistry and Molecular Biology</pub><pmid>23960078</pmid><doi>10.1074/jbc.M113.497602</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; EZB-FREE-00999 freely available EZB journals; PubMed Central; Alma/SFX Local Collection |
| subjects | Angiopoietins - isolation & purification Angiopoietins - metabolism Animals Biocatalysis Cattle Chromatography, Affinity Cross-Linking Reagents Enzyme Activation Heparin Hot Temperature Lipids Lipoprotein Lipase - antagonists & inhibitors Lipoprotein Lipase - isolation & purification Lipoprotein Lipase - metabolism Microscopy, Atomic Force Models, Biological Multiprotein Complexes - metabolism Sepharose Time Factors |
| title | Angiopoietin-like protein 4 inhibition of lipoprotein lipase: evidence for reversible complex formation |
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