Lack of Proteasome Active Site Allostery as Revealed by Subunit-Specific Inhibitors
The chymotrypsin-like (CT-L) activity of the proteasome is downregulated by substrates of the peptidyl-glutamyl peptide hydrolyzing (PGPH) activity. To investigate the nature of such interactions, we synthesized selective α′,β′-epoxyketone inhibitors of the PGPH activity. In cellular proliferation a...
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| Veröffentlicht in: | Molecular cell 2001-02, Vol.7 (2), p.411-420 |
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| creator | Myung, Jayhyuk Kim, Kyung Bo Lindsten, Kristina Dantuma, Nico P Crews, Craig M |
| description | The chymotrypsin-like (CT-L) activity of the proteasome is downregulated by substrates of the peptidyl-glutamyl peptide hydrolyzing (PGPH) activity. To investigate the nature of such interactions, we synthesized selective α′,β′-epoxyketone inhibitors of the PGPH activity. In cellular proliferation and protein degradation assays, these inhibitors revealed that selective PGPH inhibition was insufficient to inhibit protein degradation, indicating that the CT-L and PGPH sites function independently. We also demonstrated that CT-L inhibition by a PGPH substrate does not require the occupancy of the PGPH site or hydrolysis of the PGPH substrate. Thus, these results support a model in which a substrate of one subunit regulates the activity of another via binding to a noncatalytic site(s) rather than through binding to an active site. |
| doi_str_mv | 10.1016/S1097-2765(01)00188-5 |
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To investigate the nature of such interactions, we synthesized selective α′,β′-epoxyketone inhibitors of the PGPH activity. In cellular proliferation and protein degradation assays, these inhibitors revealed that selective PGPH inhibition was insufficient to inhibit protein degradation, indicating that the CT-L and PGPH sites function independently. We also demonstrated that CT-L inhibition by a PGPH substrate does not require the occupancy of the PGPH site or hydrolysis of the PGPH substrate. 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To investigate the nature of such interactions, we synthesized selective α′,β′-epoxyketone inhibitors of the PGPH activity. In cellular proliferation and protein degradation assays, these inhibitors revealed that selective PGPH inhibition was insufficient to inhibit protein degradation, indicating that the CT-L and PGPH sites function independently. We also demonstrated that CT-L inhibition by a PGPH substrate does not require the occupancy of the PGPH site or hydrolysis of the PGPH substrate. Thus, these results support a model in which a substrate of one subunit regulates the activity of another via binding to a noncatalytic site(s) rather than through binding to an active site.</description><subject>Allosteric Regulation</subject><subject>Animals</subject><subject>Binding Sites</subject><subject>Cattle</subject><subject>Cell Division - drug effects</subject><subject>Cells, Cultured</subject><subject>Chymotrypsin - antagonists & inhibitors</subject><subject>Chymotrypsin - metabolism</subject><subject>Cysteine Endopeptidases - chemistry</subject><subject>Cysteine Endopeptidases - metabolism</subject><subject>Endopeptidases - metabolism</subject><subject>Epoxy Compounds - pharmacology</subject><subject>Humans</subject><subject>Hydrolysis</subject><subject>Ketones - pharmacology</subject><subject>Kinetics</subject><subject>Models, Biological</subject><subject>Multienzyme Complexes - antagonists & inhibitors</subject><subject>Multienzyme Complexes - chemistry</subject><subject>Multienzyme Complexes - metabolism</subject><subject>Protease Inhibitors - metabolism</subject><subject>Protease Inhibitors - pharmacology</subject><subject>Proteasome Endopeptidase Complex</subject><subject>Protein Subunits</subject><subject>Recombinant Fusion Proteins - metabolism</subject><subject>Serine - analogs & derivatives</subject><subject>Serine - pharmacology</subject><subject>Substrate Specificity</subject><subject>Transfection</subject><issn>1097-2765</issn><issn>1097-4164</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>D8T</sourceid><recordid>eNqFkE1r3DAQhkVoyfdPSNGpNAcnGtvySqcSQpMGFhLi5CwkeUzVeFdbSd6y_z7aXdMec5qX4Zl34CHkAtgVMGiuW2ByVpSzhn9jcMkYCFHwA3K8W9fQ1J-mvEWOyEmMvzNUcyEPyRFAWcm6kceknWv7Rn1Pn4JPqKNfIL2xya2Rti7lPAw-JgwbqiN9xjXqATtqNrQdzbh0qWhXaF3vLH1Y_nLGJR_iGfnc6yHi-TRPyevdj5fbn8X88f7h9mZeWN7UqUAjkUNTSm0azSWAtAK6ngmwWJfYMSMsiq62TCPLsNG64p0FLgQzFe-rU1Lse-NfXI1GrYJb6LBRXjs1rd5yQsWlmEmZ-a97fhX8nxFjUgsXLQ6DXqIfo5o1MneXVQb5HrTBxxiw_1cNTG3tq519tVWrGKidfcXz3ZfpwWgW2P2_mnRn4PsewKxl7TCoaB0uLXYuoE2q8-6DF--nW5Wi</recordid><startdate>20010201</startdate><enddate>20010201</enddate><creator>Myung, Jayhyuk</creator><creator>Kim, Kyung Bo</creator><creator>Lindsten, Kristina</creator><creator>Dantuma, Nico P</creator><creator>Crews, Craig M</creator><general>Elsevier Inc</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>ADTPV</scope><scope>AOWAS</scope><scope>D8T</scope><scope>ZZAVC</scope></search><sort><creationdate>20010201</creationdate><title>Lack of Proteasome Active Site Allostery as Revealed by Subunit-Specific Inhibitors</title><author>Myung, Jayhyuk ; Kim, Kyung Bo ; Lindsten, Kristina ; Dantuma, Nico P ; Crews, Craig M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c564t-eb9e51629ab6a59119c81df081ce42ed0b8ce8d4c0ae0eb9baa35dc15880b35f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Allosteric Regulation</topic><topic>Animals</topic><topic>Binding Sites</topic><topic>Cattle</topic><topic>Cell Division - drug effects</topic><topic>Cells, Cultured</topic><topic>Chymotrypsin - antagonists & inhibitors</topic><topic>Chymotrypsin - metabolism</topic><topic>Cysteine Endopeptidases - chemistry</topic><topic>Cysteine Endopeptidases - metabolism</topic><topic>Endopeptidases - metabolism</topic><topic>Epoxy Compounds - pharmacology</topic><topic>Humans</topic><topic>Hydrolysis</topic><topic>Ketones - pharmacology</topic><topic>Kinetics</topic><topic>Models, Biological</topic><topic>Multienzyme Complexes - antagonists & inhibitors</topic><topic>Multienzyme Complexes - chemistry</topic><topic>Multienzyme Complexes - metabolism</topic><topic>Protease Inhibitors - metabolism</topic><topic>Protease Inhibitors - pharmacology</topic><topic>Proteasome Endopeptidase Complex</topic><topic>Protein Subunits</topic><topic>Recombinant Fusion Proteins - metabolism</topic><topic>Serine - analogs & derivatives</topic><topic>Serine - pharmacology</topic><topic>Substrate Specificity</topic><topic>Transfection</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Myung, Jayhyuk</creatorcontrib><creatorcontrib>Kim, Kyung Bo</creatorcontrib><creatorcontrib>Lindsten, Kristina</creatorcontrib><creatorcontrib>Dantuma, Nico P</creatorcontrib><creatorcontrib>Crews, Craig M</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Freely available online</collection><collection>SwePub Articles full text</collection><jtitle>Molecular cell</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Myung, Jayhyuk</au><au>Kim, Kyung Bo</au><au>Lindsten, Kristina</au><au>Dantuma, Nico P</au><au>Crews, Craig M</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Lack of Proteasome Active Site Allostery as Revealed by Subunit-Specific Inhibitors</atitle><jtitle>Molecular cell</jtitle><addtitle>Mol Cell</addtitle><date>2001-02-01</date><risdate>2001</risdate><volume>7</volume><issue>2</issue><spage>411</spage><epage>420</epage><pages>411-420</pages><issn>1097-2765</issn><eissn>1097-4164</eissn><abstract>The chymotrypsin-like (CT-L) activity of the proteasome is downregulated by substrates of the peptidyl-glutamyl peptide hydrolyzing (PGPH) activity. To investigate the nature of such interactions, we synthesized selective α′,β′-epoxyketone inhibitors of the PGPH activity. In cellular proliferation and protein degradation assays, these inhibitors revealed that selective PGPH inhibition was insufficient to inhibit protein degradation, indicating that the CT-L and PGPH sites function independently. We also demonstrated that CT-L inhibition by a PGPH substrate does not require the occupancy of the PGPH site or hydrolysis of the PGPH substrate. Thus, these results support a model in which a substrate of one subunit regulates the activity of another via binding to a noncatalytic site(s) rather than through binding to an active site.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>11239469</pmid><doi>10.1016/S1097-2765(01)00188-5</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Allosteric Regulation Animals Binding Sites Cattle Cell Division - drug effects Cells, Cultured Chymotrypsin - antagonists & inhibitors Chymotrypsin - metabolism Cysteine Endopeptidases - chemistry Cysteine Endopeptidases - metabolism Endopeptidases - metabolism Epoxy Compounds - pharmacology Humans Hydrolysis Ketones - pharmacology Kinetics Models, Biological Multienzyme Complexes - antagonists & inhibitors Multienzyme Complexes - chemistry Multienzyme Complexes - metabolism Protease Inhibitors - metabolism Protease Inhibitors - pharmacology Proteasome Endopeptidase Complex Protein Subunits Recombinant Fusion Proteins - metabolism Serine - analogs & derivatives Serine - pharmacology Substrate Specificity Transfection |
| title | Lack of Proteasome Active Site Allostery as Revealed by Subunit-Specific Inhibitors |
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