U2AF-homology motif interactions are required for alternative splicing regulation by SPF45

Corsini, Lorenzo; Bonnal, Sophie; Basquin, J.; Hothorn, Michael; Scheffzek, Klaus; Valcárcel, Juan; Sattler, Michael

doi:10.1038/nsmb1260

Cited by 149 publications

(256 citation statements)

References 46 publications

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“…2d). In contrast, Bud13p might not only bind to Snu17p within the RES complex but also engage in interactions with other proteins, possibly via the canonical mode, in agreement with the ability of single ULMs to bind to different UHMs 21,23 .…”

Section: Discussionmentioning

confidence: 87%

“…Sequence homology of Bud13p to ligands that bind to U2AF-homology motifs of RRM domains suggested that Bud13p interacts with Snu17p according to canonical UHM-ULM interactions (Fig. 6b,d) 13,15,16,[18][19][20][21][22] . However, the three-dimensional structure of the RES core complex demonstrated a distinct interaction mode unlike that of UHM and ULM (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…1a and 2b). In canonical UHM-ULM interactions, the ULM is formed by a positively charged sequence followed by an essential tryptophan [18][19][20][21][22] . In Bud13p the tryptophan is located at position 232, and it was supposed to bind to the hydrophobic pocket between α-helices 1 and 2 (refs.…”

Section: Structure Of the Res Core Complexmentioning

confidence: 99%

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Cooperative structure of the heterotrimeric pre-mRNA retention and splicing complex

Wysoczanski

Schneider

Munari

et al. 2014

Nat Struct Mol Biol

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1 1 a r t i c l e sSplicing entails the removal of introns from pre-mRNAs to generate exon-only mRNA, which is exported out of the nucleus for translation 1 . The splicing process is driven and controlled by a large and dynamic RNA-protein complex, the spliceosome 1,2 . The composition and structure of the spliceosome undergoes multiple rearrangements during a splicing reaction, in which a set of distinct structural and compositional states, designated as E, A, B act , B* and C complexes, can be defined 1 . As part of this process, small nuclear ribonucleoprotein (snRNP) particles and non-snRNP splice factors are recruited and released 1,2 . Although the organization of snRNP components of the spliceosome has received considerable attention in recent years, very little is known about the assembly, structure and dynamics of non-snRNP multimeric complexes.The non-snRNP RES complex is present in humans and yeast 3,4 . Deletion of RES genes slows splicing and leads to pre-mRNA leakage into the cytoplasm 3-5 . Distinct introns exhibit RES-dependent splicing 5-9 , as do pre-mRNAs encoding proteins functioning in RNA-nucleotide metabolism 8,10 . Components of the RES complex are found in B and C complexes of the spliceosome, in which RES can interact with U2 snRNP 4,11,12 . In yeast, the RES complex is composed of three proteins, snRNP-associated protein 17 (Snu17p, also known as Ist3p), pre-mRNA-leakage protein 1 (Pml1p) and bud siteselection protein 13 (Bud13p) 3,4 . Snu17p and Bud13p have been implicated directly in splicing 3,5,13 , whereas Pml1p has been linked to the retention of unspliced pre-mRNA in the nucleus 3,5 . Caenorhabditis elegans Bud13p is involved in embryogenesis 14 .Sequence analysis has indicated that Snu17p is a 148-residue (17.1-kDa) noncanonical member of the RRM family of proteins with a long C-terminal part, which exhibits low sequence similarity to published RRM structures 4 . Snu17p binds with nanomolar affinity to the 266-residue (30.5-kDa), natively disordered protein Bud13p 15 . The interaction has been postulated to involve a C-terminal UHM-ligand motif (ULM) in Bud13p that interacts with a U2AF-homology motif (UHM) in the RRM domain of Snu17p 13,15,16 . The only other identified domain encompasses a stretch of lysine residues at the N terminus of Bud13p. Binding of the third component, the 204-residue (23.4-kDa) Pml1p, occurs through its 50 N-terminal disordered residues. The remainder of Pml1p folds as a forkhead-associated domain 13,15,17 , which could potentially bind phosphopeptides 17 . Biochemical evidence has suggested that Snu17p acts as the central binding platform, which interacts with disordered parts of Bud13p and Pml1p 13,15,16 . The precise molecular architecture of the RES complex, however, has been elusive, and its RNA binding capabilities have remained unexplored.Here we solved the three-dimensional structure of the core of the RES complex and demonstrated that its assembly is driven by cooperativity that increases the binding affinity of the components of the complex ...

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

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Cooperative structure of the heterotrimeric pre-mRNA retention and splicing complex

Wysoczanski

Schneider

Munari

et al. 2014

Nat Struct Mol Biol

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“…In mammalian U2AF large subunit, the corresponding residues of the four amino acids are M110, S142, M144 and T145, respectively [35,51]. M110 is a conserved residue in the UHM-ligand motif (ULM) [52], which is also known as the ‘U2AF small subunit-interacting domain’ [35,53]. S142, M144 and T145 are located in a small region between ULM and RRM1 of the U2AF large subunit, the function of which is unclear.…”

Section: Discussionmentioning

confidence: 99%

RBM-5 modulates U2AF large subunit-dependent alternative splicing inC. elegans

Zhou

Gao

et al. 2018

RNA Biology

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A key step in pre-mRNA splicing is the recognition of 3ʹ splicing sites by the U2AF large and small subunits, a process regulated by numerous trans-acting splicing factors. How these trans-acting factors interact with U2AF in vivo is unclear. From a screen for suppressors of the temperature-sensitive (ts) lethality of the C. elegans U2AF large subunit gene uaf-1(n4588) mutants, we identified mutations in the RNA binding motif gene rbm-5, a homolog of the tumor suppressor gene RBM5. rbm-5 mutations can suppress uaf-1(n4588) ts-lethality by loss of function and neuronal expression of rbm-5 was sufficient to rescue the suppression. Transcriptome analyses indicate that uaf-1(n4588) affected the expression of numerous genes and rbm-5 mutations can partially reverse the abnormal gene expression to levels similar to that of wild type. Though rbm-5 mutations did not obviously affect alternative splicing per se, they can suppress or enhance, in a gene-specific manner, the altered splicing of genes in uaf-1(n4588) mutants. Specifically, the recognition of a weak 3ʹ splice site was more susceptible to the effect of rbm-5. Our findings provide novel in vivo evidence that RBM-5 can modulate UAF-1-dependent RNA splicing and suggest that RBM5 might interact with U2AF large subunit to affect tumor formation.

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“…Examples include SPF45 (also called RBM17 and a homolog of DRT111) ( Fig. 2E; Corsini et al 2007), PUF60 (also called FIR) (Corsini et al 2009), and CAPERα (also called HCC1 or RBM39 and a homolog of PAD-1) ( Fig. 2F; Loerch et al 2014).…”

Section: Introductionmentioning

confidence: 99%

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

Loerch

Kielkopf

2016

RNA

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U2AF homology motifs (UHM) that recognize U2AF ligand motifs (ULM) are an emerging family of protein-protein interaction modules. UHM-ULM interactions recur in pre-mRNA splicing factors including U2AF1 and SF3b1, which are frequently mutated in myelodysplastic syndromes. The core topology of the UHM resembles an RNA recognition motif and is often mistakenly classified within this large family. Here, we unmask the charade and review recent discoveries of UHM-ULM modules for protein-protein interactions. Diverse polypeptide extensions and selective phosphorylation of UHM and ULM family members offer new molecular mechanisms for the assembly of specific partners in the early-stage spliceosome.

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U2AF-homology motif interactions are required for alternative splicing regulation by SPF45

Cited by 149 publications

References 46 publications

Cooperative structure of the heterotrimeric pre-mRNA retention and splicing complex

Cooperative structure of the heterotrimeric pre-mRNA retention and splicing complex

RBM-5 modulates U2AF large subunit-dependent alternative splicing inC. elegans

Unmasking the U2AF homology motif family: a bona fide protein–protein interaction motif in disguise

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