Structure and function of WD40 domain proteins

Xu, Chao; Min, Jinrong

doi:10.1007/s13238-011-1018-1

Cited by 543 publications

(524 citation statements)

References 82 publications

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“…2C), six of which are composed of four β-strands, with the last β-sheet containing only three ordered strands; the first 12 and last 13 residues are disordered and not visible in the electron density. The structure therefore lacks the "velcro" closure seen in the majority of WD40 domains, where the three strands from the last blade form a β-sheet with the strand that precedes the first blade (22,37). The sequence motifs that characterize the WD40 domain are scarce in MEP50, with only two of the seven blades containing the WD motif at the end of the third strand.…”

Section: Resultsmentioning

confidence: 99%

“…WD40 proteins are known to play vital roles in various cellular networks (20,21). These proteins function as protein-protein and protein-DNA interaction platforms and also as recognition modules of posttranslational modifications (22,23). Recent studies on MEP50 identified the presence of two nuclear exclusion signals and three nuclear localization signals that control its subcellular localization and its function as a transcriptional cofactor of androgen receptor during prostate development and tumorigenesis (24).…”

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confidence: 99%

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Crystal structure of the human PRMT5:MEP50 complex

Antonysamy

Bonday

Campbell

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

280

385

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Protein arginine methyltransferases (PRMTs) play important roles in several cellular processes, including signaling, gene regulation, and transport of proteins and nucleic acids, to impact growth, differentiation, proliferation, and development. PRMT5 symmetrically di-methylates the two-terminal ω-guanidino nitrogens of arginine residues on substrate proteins. PRMT5 acts as part of a multimeric complex in concert with a variety of partner proteins that regulate its function and specificity. A core component of these complexes is the WD40 protein MEP50/WDR77/p44, which mediates interactions with binding partners and substrates. We have determined the crystal structure of human PRMT5 in complex with MEP50 (methylosome protein 50), bound to an S-adenosylmethionine analog and a peptide substrate derived from histone H4. The structure of the surprising hetero-octameric complex reveals the close interaction between the seven-bladed β-propeller MEP50 and the N-terminal domain of PRMT5, and delineates the structural elements of substrate recognition.epigenetics | protein-protein complex | A9145C P osttranslational methylation of lysine and arginine residues by protein lysine methyltransferases and protein arginine methyltransferases (PRMTs) alters the activity and interactions of substrate proteins, with crucial consequences to diverse cellular functions (1-3). Histone methylation is an epigenetic mark that plays a vital role in normal cell function, and whose dysregulation is associated with several diseases (4).The PRMT family of methyltransferases belongs to the largest class (class I) of S-adenosylmethionine (AdoMet)-dependent methyltransferase enzymes, responsible for the transfer of a methyl group from AdoMet to the arginine side-chains of histones and other proteins. PRMTs are further subdivided into type I, type II, type III, and type IV enzymes based on their patterns of arginine methylation. Eleven human PRMTs have been identified to date (5), and they all methylate the terminal guanidino nitrogen atoms of arginine residues. Type I PRMT enzymes (PRMT1, -2, -3, -4, -6, and -8) generate ω-NG-monomethyl and ω-NG,NG-asymmetric di-methyl arginines, whereas PRMT5 is a type II PRMT that catalyzes the formation of ω-NG-monomethyl and ω-NG,N′G-symmetric di-methyl arginine residues. PRMT7 was initially thought to have type II activity, but recent evidence suggests that it may be a type III enzyme that is only able to monomethylate substrates to form ω-NG-monomethyl arginine (6). A type IV enzyme that catalyses the formation of δ-N-methyl arginine has been identified in yeast (7). All PRMTs share the highly conserved methyltransferase catalytic domain, and several PRMTs contain additional domains that modulate their activity and specificity. PRMT2, PRMT3, and PRMT9 contain SH3, zinc finger, and TRP2 domains, respectively, and PRMT5 contains a largely uncharacterized N-terminal region.In contrast to type I PRMTs, PRMT5 functions as part of various high molecular weight protein complexes that invariably contain the WD-repe...

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Crystal structure of the human PRMT5:MEP50 complex

Antonysamy

Bonday

Campbell

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

280

385

View full text Add to dashboard Cite

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“…48 WD40 domains exist in a wide variety of eukaryotic proteins and typically form a seven bladed bpropeller structure to which proteins can bind either stably or reversibly. 53 Most likely, the WD40 domain of ALFY can form a complete b-propeller structure without having seven WD40 repeats, but it also possible that WD40 repeats need to be donated from other interaction partners to complete the b-propeller. Finally, ALFY contains a PH-like domain followed by a BEACH domain.…”

Section: Adaptor Proteinsmentioning

confidence: 99%

The role of ALFY in selective autophagy

2012

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Autophagy, a highly conserved lysosomal degradation pathway, was initially characterized as a bulk degradation system induced in response to starvation. In recent years, autophagy has emerged also as a highly selective pathway, targeting various cargoes such as aggregated proteins and damaged organelles for degradation. The key factors involved in selective autophagy are autophagy receptors and adaptor proteins, which connect the cargo to the core autophagy machinery. In this review, we discuss the current knowledge about the only mammalian adaptor protein identified thus far, autophagy-linked FYVE protein (ALFY). ALFY is a large, scaffolding, multidomain protein implicated in the selective degradation of ubiquitinated protein aggregates by autophagy. We also comment on the possible role of ALFY in the context of disease.

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“…The blades assemble to form a toroidally shaped structure with a solvent accessible central channel, where one side of the toroid is wider ("wide" side) than the other side ("narrow" side). In general, the surfaces of the wide and narrow sides contain loops that connect the β strands and are important for either protein-protein or proteinnucleic acid interactions (27). Similar to other β-propellers, the N and C termini of Dos1WD come together to form the last blade, known as the "velcro closure," which has been shown to stabilize the β-propeller (27).…”

Section: Wd Repeat Domain Of Dos1mentioning

confidence: 99%

“…S3). Because the loops on the β-propellers are frequently involved in target recognition (27), these disordered and flexible loops on the narrow side of Dos1WD are expected to be important for Dos1 function.…”

Section: Wd Repeat Domain Of Dos1mentioning

confidence: 99%

CRL4-like Clr4 complex in Schizosaccharomyces pombe depends on an exposed surface of Dos1 for heterochromatin silencing

Kuscu

Zaratiegui

Kim

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance The CLRC complex is essential for heterochromatin formation in the yeast Schizosaccharomyces pombe. Its well-known role in placing methyl marks on histone H3 lysine 9 at heterochromatic loci is attributed to one of its components, cryptic loci regulator 4. However, it also contains an E3 ubiquitin ligase, a less understood activity of this complex. Here, we describe the organization of this seven-component complex and determine the crystal structure of delocalization of Swi6 1 (Dos1), a key subunit involved in targeting CLRC. We identify Dos2 as the central component of the complex and point of contact with Stc1, which bridges CLRC to the RNAi-induced transcriptional silencing complex, and show that heterochromatin formation is dependent on an exposed surface of Dos1. These results provide an unprecedented, high-resolution functional annotation of CLRC.

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Structure and function of WD40 domain proteins

Cited by 543 publications

References 82 publications

Crystal structure of the human PRMT5:MEP50 complex

Crystal structure of the human PRMT5:MEP50 complex

The role of ALFY in selective autophagy

CRL4-like Clr4 complex in Schizosaccharomyces pombe depends on an exposed surface of Dos1 for heterochromatin silencing

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