TY - JOUR
T1 - Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrm1
AU - Yao, Tingting
AU - Song, Ling
AU - Xu, Wei
AU - DeMartino, George N.
AU - Florens, Laurence
AU - Swanson, Selene K.
AU - Washburn, Michael P.
AU - Conaway, Ronald C.
AU - Conaway, Joan Weliky
AU - Cohen, Robert E.
N1 - Funding Information:
We thank C. Gorbea and M. Rechsteiner for plasmids containing 19S complex cDNAs, A. Borodovsky and H. Ploegh for UbVS, B. Plapp for advice on fitting kinetic data and C. Slaughter for mass spectrometry of Uch37 peptides. This work was supported, in part, by the National Institutes of Health grants R01 GM37666 (to R.E.C.) and R37 GM41628 (to R.C.C.). T.Y. is a fellow of the Leukemia and Lymphoma Society.
PY - 2006/9
Y1 - 2006/9
N2 - Uch37 is one of the three principal deubiquitinating enzymes (DUBs), and the only ubiquitin carboxy-terminal hydrolase (UCH)-family protease, that is associated with mammalian proteasomes. We show that Uch37 is responsible for the ubiquitin isopeptidase activity in the PA700 (19S) proteasome regulatory complex1. PA700 isopeptidase disassembles Lys 48-linked polyubiquitin specifically from the distal end of the chain, a property that may be used to clear poorly ubiquitinated or unproductively bound substrates from the proteasome. To better understand Uch37 function and the mechanism responsible for its specificity, we investigated how Uch37 is recruited to proteasomes. Uch37 binds through Adrm1, a previously unrecognized orthologue of Saccharomyces cerevisiae Rpn13p, which in turn is bound to the S1 (also known as Rpn2) subunit of the 19S complex. Adrm1 (human Rpn13, hRpn13) binds the carboxy-terminal tail of Uch37, a region that is distinct from the UCH catalytic domain, which we show inhibits Uch37 activity. Following binding, Adrm1 relieves Uch37 autoinhibition, accelerating the hydrolysis of ubiquitin-7-amido-4-methylcoumarin (ubiquitin-AMC). However, neither Uch37 alone nor the Uch37-Adrm1 or Uch37-Adrm1-S1 complexes can hydrolyse di-ubiquitin efficiently; rather, incorporation into the 19S complex is required to enable processing of polyubiquitin chains.
AB - Uch37 is one of the three principal deubiquitinating enzymes (DUBs), and the only ubiquitin carboxy-terminal hydrolase (UCH)-family protease, that is associated with mammalian proteasomes. We show that Uch37 is responsible for the ubiquitin isopeptidase activity in the PA700 (19S) proteasome regulatory complex1. PA700 isopeptidase disassembles Lys 48-linked polyubiquitin specifically from the distal end of the chain, a property that may be used to clear poorly ubiquitinated or unproductively bound substrates from the proteasome. To better understand Uch37 function and the mechanism responsible for its specificity, we investigated how Uch37 is recruited to proteasomes. Uch37 binds through Adrm1, a previously unrecognized orthologue of Saccharomyces cerevisiae Rpn13p, which in turn is bound to the S1 (also known as Rpn2) subunit of the 19S complex. Adrm1 (human Rpn13, hRpn13) binds the carboxy-terminal tail of Uch37, a region that is distinct from the UCH catalytic domain, which we show inhibits Uch37 activity. Following binding, Adrm1 relieves Uch37 autoinhibition, accelerating the hydrolysis of ubiquitin-7-amido-4-methylcoumarin (ubiquitin-AMC). However, neither Uch37 alone nor the Uch37-Adrm1 or Uch37-Adrm1-S1 complexes can hydrolyse di-ubiquitin efficiently; rather, incorporation into the 19S complex is required to enable processing of polyubiquitin chains.
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U2 - 10.1038/ncb1460
DO - 10.1038/ncb1460
M3 - Article
C2 - 16906146
AN - SCOPUS:33748188085
SN - 1465-7392
VL - 8
SP - 994
EP - 1002
JO - Nature cell biology
JF - Nature cell biology
IS - 9
ER -