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Cancer-relevant splicing factor CAPER? engages the essential splicing factor
SF3b155 in a specific ternary complex
#MMPMID24795046
Loerch S
; Maucuer A
; Manceau V
; Green MR
; Kielkopf CL
J Biol Chem
2014[Jun]; 289
(25
): 17325-37
PMID24795046
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U2AF homology motifs (UHMs) mediate protein-protein interactions with U2AF ligand
motifs (ULMs) of pre-mRNA splicing factors. The UHM-containing alternative
splicing factor CAPER? regulates splicing of tumor-promoting VEGF isoforms, yet
the molecular target of the CAPER? UHM is unknown. Here we present structures of
the CAPER? UHM bound to a representative SF3b155 ULM at 1.7 Å resolution and, for
comparison, in the absence of ligand at 2.2 Å resolution. The prototypical
UHM/ULM interactions authenticate CAPER? as a bona fide member of the UHM family
of proteins. We identify SF3b155 as the relevant ULM-containing partner of
full-length CAPER? in human cell extracts. Isothermal titration calorimetry
comparisons of the purified CAPER? UHM binding known ULM-containing proteins
demonstrate that high affinity interactions depend on the presence of an intact,
intrinsically unstructured SF3b155 domain containing seven ULM-like motifs. The
interplay among bound CAPER? molecules gives rise to the appearance of two high
affinity sites in the SF3b155 ULM-containing domain. In conjunction with the
previously identified, UHM/ULM-mediated complexes of U2AF(65) and SPF45 with
SF3b155, this work demonstrates the capacity of SF3b155 to offer a platform for
coordinated recruitment of UHM-containing splicing factors.
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