Derepression by depolymerization; structural insights into the regulation of Yan by Mae.
Yan, an ETS family transcriptional repressor, is regulated by receptor tyrosine kinase signaling via the Ras/MAPK pathway. Phosphorylation and downregulation of Yan is facilitated by a protein called Mae. Yan and Mae interact through their SAM domains. We find that repression by Yan requires the formation of a higher order structure mediated by Yan-SAM polymerization. Moreover, a crystal structure of the Yan-SAM/Mae-SAM complex shows that Mae-SAM specifically recognizes a surface on Yan-SAM that is also required for Yan-SAM polymerization. Mae-SAM binds to Yan-SAM with approximately 1000-fold higher affinity than Yan-SAM binds to itself and can effectively depolymerize Yan-SAM. Mutations on Mae that specifically disrupt its SAM domain-dependent interactions with Yan disable the derepression function of Mae in vivo. Depolymerization of Yan by Mae represents a novel mechanism of transcriptional control that sensitizes Yan for regulation by receptor tyrosine kinases.
Qiao
Feng
F
UCLA-DOE Institute of Genomics and Proteomics, Molecular Biology Institute, Department of Chemistry and Biochemistry, University of California, Los Angeles 90095, USA.
Song
Haiyun
H
Kim
Chongwoo A
CA
Sawaya
Michael R
MR
Hunter
Jacob B
JB
Gingery
Mari
M
Rebay
Ilaria
I
Courey
Albert J
AJ
Bowie
James U
JU
D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D004330:Drosophila; D029721:Drosophila Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005136:Eye Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D005809:Genes, Regulator / Q000502:physiology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008958:Models, Molecular; D015394:Molecular Structure; D009154:Mutation / Q000235:genetics; D011108:Polymers / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D020349:Surface Plasmon Resonance
C076188:AOP protein, Drosophila; D002352:Carrier Proteins; D029721:Drosophila Proteins; D005136:Eye Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011108:Polymers; D012097:Repressor Proteins; C428945:edl protein, Drosophila; D020794:Receptor Protein-Tyrosine Kinases