TY - JOUR
T1 - Trans-Binding Mechanism of Ubiquitin-like Protein Activation Revealed by a UBA5-UFM1 Complex
AU - Oweis, Walaa
AU - Padala, Prasanth
AU - Hassouna, Fouad
AU - Cohen-Kfir, Einav
AU - Gibbs, Dalton R.
AU - Todd, Emily A.
AU - Berndsen, Christopher E.
AU - Wiener, Reuven
N1 - Publisher Copyright:
© 2016 The Author(s)
PY - 2016/9/20
Y1 - 2016/9/20
N2 - Modification of proteins by ubiquitin or ubiquitin-like proteins (UBLs) is a critical cellular process implicated in a variety of cellular states and outcomes. A prerequisite for target protein modification by a UBL is the activation of the latter by activating enzymes (E1s). Here, we present the crystal structure of the non-canonical homodimeric E1, UBA5, in complex with its cognate UBL, UFM1, and supporting biochemical experiments. We find that UBA5 binds to UFM1 via a trans-binding mechanism in which UFM1 interacts with distinct sites in both subunits of the UBA5 dimer. This binding mechanism requires a region C-terminal to the adenylation domain that brings UFM1 to the active site of the adjacent UBA5 subunit. We also find that transfer of UFM1 from UBA5 to the E2, UFC1, occurs via a trans mechanism, thereby requiring a homodimer of UBA5. These findings explicitly elucidate the role of UBA5 dimerization in UFM1 activation.
AB - Modification of proteins by ubiquitin or ubiquitin-like proteins (UBLs) is a critical cellular process implicated in a variety of cellular states and outcomes. A prerequisite for target protein modification by a UBL is the activation of the latter by activating enzymes (E1s). Here, we present the crystal structure of the non-canonical homodimeric E1, UBA5, in complex with its cognate UBL, UFM1, and supporting biochemical experiments. We find that UBA5 binds to UFM1 via a trans-binding mechanism in which UFM1 interacts with distinct sites in both subunits of the UBA5 dimer. This binding mechanism requires a region C-terminal to the adenylation domain that brings UFM1 to the active site of the adjacent UBA5 subunit. We also find that transfer of UFM1 from UBA5 to the E2, UFC1, occurs via a trans mechanism, thereby requiring a homodimer of UBA5. These findings explicitly elucidate the role of UBA5 dimerization in UFM1 activation.
UR - http://www.scopus.com/inward/record.url?scp=84989866472&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2016.08.067
DO - 10.1016/j.celrep.2016.08.067
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C2 - 27653677
AN - SCOPUS:84989866472
SN - 2211-1247
VL - 16
SP - 3113
EP - 3120
JO - Cell Reports
JF - Cell Reports
IS - 12
ER -