Title | S. pombe Uba1-Ubc15 Structure Reveals a Novel Regulatory Mechanism of Ubiquitin E2 Activity. |
Publication Type | Journal Article |
Year of Publication | 2017 |
Authors | Lv Z, Rickman KA, Yuan L, Williams K, Selvam SPanneer, Woosley AN, Howe PH, Ogretmen B, Smogorzewska A, Olsen SK |
Journal | Mol Cell |
Volume | 65 |
Issue | 4 |
Pagination | 699-714.e6 |
Date Published | 2017 Feb 16 |
ISSN | 1097-4164 |
Keywords | Binding Sites, Cell Line, Humans, Models, Molecular, Phosphorylation, Protein Binding, Protein Interaction Domains and Motifs, Schizosaccharomyces, Schizosaccharomyces pombe Proteins, Structure-Activity Relationship, Transfection, Ubiquitin, Ubiquitin-Activating Enzymes, Ubiquitin-Conjugating Enzymes, Ubiquitin-Protein Ligases, Ubiquitination |
Abstract | Ubiquitin (Ub) E1 initiates the Ub conjugation cascade by activating and transferring Ub to tens of different E2s. How Ub E1 cooperates with E2s that differ substantially in their predicted E1-interacting residues is unknown. Here, we report the structure of S. pombe Uba1 in complex with Ubc15, a Ub E2 with intrinsically low E1-E2 Ub thioester transfer activity. The structure reveals a distinct Ubc15 binding mode that substantially alters the network of interactions at the E1-E2 interface compared to the only other available Ub E1-E2 structure. Structure-function analysis reveals that the intrinsically low activity of Ubc15 largely results from the presence of an acidic residue at its N-terminal region. Notably, Ub E2 N termini are serine/threonine rich in many other Ub E2s, leading us to hypothesize that phosphorylation of these sites may serve as a novel negative regulatory mechanism of Ub E2 activity, which we demonstrate biochemically and in cell-based assays. |
DOI | 10.1016/j.molcel.2017.01.008 |
Alternate Journal | Mol. Cell |
PubMed ID | 28162934 |
PubMed Central ID | PMC5319395 |
Grant List | UL1 TR000043 / TR / NCATS NIH HHS / United States R01 CA173687 / CA / NCI NIH HHS / United States R01 HL120922 / HL / NHLBI NIH HHS / United States R01 CA088932 / CA / NCI NIH HHS / United States UL1 TR001866 / TR / NCATS NIH HHS / United States S10 RR027139 / RR / NCRR NIH HHS / United States P30 CA138313 / CA / NCI NIH HHS / United States P01 CA203628 / CA / NCI NIH HHS / United States R01 GM115568 / GM / NIGMS NIH HHS / United States R01 CA154663 / CA / NCI NIH HHS / United States T32 GM007739 / GM / NIGMS NIH HHS / United States R01 CA055536 / CA / NCI NIH HHS / United States R01 DE016572 / DE / NIDCR NIH HHS / United States |
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