4bld
From Proteopedia
Crystal structure of a human Suppressor of fused (SUFU)-GLI3p complex
Structural highlights
Disease[GLI3_HUMAN] Postaxial polydactyly type B, unilateral;Postaxial polydactyly type A, unilateral;Pallister-Hall syndrome;Postaxial polydactyly type A, bilateral;Polysyndactyly, bilateral;Polysyndactyly, unilateral;Greig cephalopolysyndactyly syndrome;Acrocallosal syndrome;Postaxial polydactyly type B, bilateral. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry. Function[MALE_ECOLI] Involved in the high-affinity maltose membrane transport system MalEFGK. Initial receptor for the active transport of and chemotaxis toward maltooligosaccharides. [GLI3_HUMAN] Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development. The full-length GLI3 form (GLI3FL) after phosphorylation and nuclear translocation, acts as an activator (GLI3A) while GLI3R, its C-terminally truncated form, acts as a repressor. A proper balance between the GLI3 activator and the repressor GLI3R, rather than the repressor gradient itself or the activator/repressor ratio gradient, specifies limb digit number and identity. In concert with TRPS1, plays a role in regulating the size of the zone of distal chondrocytes, in restricting the zone of PTHLH expression in distal cells and in activating chondrocyte proliferation. Binds to the minimal GLI-consensus sequence 5'-GGGTGGTC-3'.[1] [2] [3] Publication Abstract from PubMedHedgehog signalling plays a fundamental role in the control of metazoan development, cell proliferation and differentiation, as highlighted by the fact that its deregulation is associated with the development of many human tumours. SUFU is an essential intracellular negative regulator of mammalian Hedgehog signalling and acts by binding and modulating the activity of GLI transcription factors. Despite its central importance, little is known about SUFU regulation and the nature of SUFU-GLI interaction. Here, the crystal and small-angle X-ray scattering structures of full-length human SUFU and its complex with the key SYGHL motif conserved in all GLIs are reported. It is demonstrated that GLI binding is associated with major conformational changes in SUFU, including an intrinsically disordered loop that is also crucial for pathway activation. These findings reveal the structure of the SUFU-GLI interface and suggest a mechanism for an essential regulatory step in Hedgehog signalling, offering possibilities for the development of novel pathway modulators and therapeutics. Structural basis of SUFU-GLI interaction in human Hedgehog signalling regulation.,Cherry AL, Finta C, Karlstrom M, Jin Q, Schwend T, Astorga-Wells J, Zubarev RA, Del Campo M, Criswell AR, de Sanctis D, Jovine L, Toftgard R Acta Crystallogr D Biol Crystallogr. 2013 Dec;69(Pt 12):2563-79. doi:, 10.1107/S0907444913028473. Epub 2013 Nov 19. PMID:24311597[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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