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Structural analysis of UBL5, a novel ubiquitin-like modifier.

ABSTRACT: UBL5 is a widely expressed human protein that is strongly conserved across phylogeny. Orthologs of UBL5 occur in every eukaryotic genome characterized to date. The yeast ortholog of UBL5, HUB1, was reported to be a ubiquitin-like protein modifier important for modulation of protein function. However, unlike ubiquitin and all other ubiquitin-like modifiers, UBL5 and its yeast ortholog HUB1 both contain a C-terminal di-tyrosine motif followed by a single variable residue instead of the characteristic di-glycine found in all other ubiquitin-like modifiers. Here we describe the three-dimensional structure of UBL5 determined by NMR. The overall structure of the protein was found to be very similar to ubiquitin despite the low approximately 25% residue similarity. The signature C-terminal di-tyrosine residues in UBL5 are involved in the final beta sheet of the protein. This is very different to the di-glycine motif found in ubiquitin, which extends beyond the final beta sheet. In addition, we have confirmed an earlier report of an interaction between UBL5 and the cyclin-like kinase, CLK4, which we have determined is specific and does not extend to other cyclin-like kinase family members.

SUBMITTER: McNally T

PROVIDER: S-EPMC2323916 | biostudies-literature | 2003 Jul

REPOSITORIES: biostudies-literature

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Structural analysis of UBL5, a novel ubiquitin-like modifier.

McNally Teresa T Huang Qiulong Q Janis Richard S RS Liu Zhihong Z Olejniczak Edward T ET Reilly Regina M RM

Protein science : a publication of the Protein Society 20030701 7

UBL5 is a widely expressed human protein that is strongly conserved across phylogeny. Orthologs of UBL5 occur in every eukaryotic genome characterized to date. The yeast ortholog of UBL5, HUB1, was reported to be a ubiquitin-like protein modifier important for modulation of protein function. However, unlike ubiquitin and all other ubiquitin-like modifiers, UBL5 and its yeast ortholog HUB1 both contain a C-terminal di-tyrosine motif followed by a single variable residue instead of the characteris ...[more]

PMID: 12824502

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Project description:Post-translational protein modifications (PTMs) including small chemical groups and small proteins, belonging to the ubiquitin family, are essential for virtually all cellular processes. In addition to modification by a single PTM, proteins can be modified by a combination of different modifiers, which are able to influence each other. Because little is known about crosstalk among different ubiquitin family members, we developed an improved method enabling identification of co-modified proteins on a system-wide level using mass spectrometry. We focused on the role of crosstalk between SUMO and ubiquitin during proteasomal degradation. Using two complementary approaches, we identified 498 proteins to be significantly co-modified by SUMO and ubiquitin upon MG132 treatment. These targets included many enzymatic components of PTM machinery, involved in SUMOylation and ubiquitylation, but also phosphorylation, methylation and acetylation, revealing a highly complex interconnected network of crosstalk among different PTMs. In addition, various other biological processes were found to be significantly enriched within the group of co-modified proteins, including transcription, DNA repair and the cell cycle. Interestingly, the latter group mostly consisted of proteins involved in mitosis, including a subset of chromosome segregation regulators. We hypothesize that group modification by SUMO-targeted ubiquitin ligases regulates the stability of the identified subset of mitotic proteins, which ensures proper chromosome segregation. The mitotic regulators KIF23 and MIS18BP1 were verified to be co-modified by SUMO and ubiquitin on inhibition of the proteasome and subsequently identified as novel RNF4 targets. Both modifications on MIS18BP1 were observed to increase simultaneously during late mitosis, whereas the total protein level decreased immediately afterward. These results confirm the regulation of MIS18BP1 via SUMO-ubiquitin crosstalk during mitosis. Combined, our work highlights extensive crosstalk between SUMO and ubiquitin, providing a resource for further unraveling of SUMO-ubiquitin crosstalk.

Dataset Information

Structural analysis of UBL5, a novel ubiquitin-like modifier.

Publications

Structural analysis of UBL5, a novel ubiquitin-like modifier.

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