A small conserved surface in SUMO is the critical structural determinant of its transcriptional inhibitory properties.
Small ubiquitin-like modifier (SUMO) modification of sequence-specific transcription factors has profound regulatory consequences. By providing an intrinsic inhibitory function, SUMO isoforms can suppress transcriptional activation, particularly at promoters harboring multiple response elements. Through a comprehensive structure-function analysis, we have identified a single critical sector along the second beta sheet and the following alpha helix of SUMO2. This distinct surface is defined by four basic residues (K33, K35, K42, R50) that surround a shallow pocket lined by aliphatic (V30, I34) and polar (T38) residues. Substitutions within this area specifically and dramatically affected the ability of both SUMO2 and SUMO1 to inhibit transcription and revealed that the positively charged nature of the key basic residues is the main feature responsible for their functional role. This highly conserved surface accounts for the inhibitory properties of SUMO on multiple transcription factors and promoter contexts and likely defines the interaction surface for the corepressors that mediate the inhibitory properties of SUMO.
Chupreta
Sergey
S
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-0632, USA.
Holmstrom
Sam
S
Subramanian
Lalitha
L
Iñiguez-Lluhí
Jorge A
JA
D000595:Amino Acid Sequence; D001665:Binding Sites; D017124:Conserved Sequence / Q000235:genetics; D015536:Down-Regulation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D025842:SUMO-1 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D025841:Small Ubiquitin-Related Modifier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D055672:Static Electricity; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic
D012097:Repressor Proteins; D025842:SUMO-1 Protein; C117909:SUMO2 protein, human; D025841:Small Ubiquitin-Related Modifier Proteins