ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures

Landau, Meytal; Mayrose, Itay; Rosenberg, Yossi; Glaser, Fabian; Martz, Eric; Pupko, Tal; Ben‐Tal, Nir

doi:10.1093/nar/gki370

Cited by 1,276 publications

(1,217 citation statements)

References 27 publications

(45 reference statements)

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“…4D), enabling recognition of the cluster of basic residues in the NID. Surface conservation calculations using vertebrate TBLR1 sequences show that the top face is conserved, consistent with a role in protein-protein interactions (29) (Fig. 4E).…”

Section: Mecp2supporting

confidence: 53%

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Kruusvee

Lyst

Taylor

et al. 2017

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

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Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. The majority of RTT missense mutations disrupt the interaction of the MeCP2 with DNA or the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid receptors (SMRT) corepressor complex. Here, we show that the "NCoR/SMRT interaction domain" (NID) of MeCP2 directly contacts transducin beta-like 1 (TBL1) and TBL1 related (TBLR1), two paralogs that are core components of NCoR/SMRT. We determine the cocrystal structure of the MeCP2 NID in complex with the WD40 domain of TBLR1 and confirm by in vitro and ex vivo assays that mutation of interacting residues of TBLR1 and TBL1 disrupts binding to MeCP2. Strikingly, the four MeCP2-NID residues mutated in RTT are those residues that make the most extensive contacts with TBLR1. Moreover, missense mutations in the gene for TBLR1 that are associated with intellectual disability also prevent MeCP2 binding. Our study therefore reveals the molecular basis of an interaction that is crucial for optimal brain function.T he methyl-CpG-binding protein 2 (MeCP2) is a chromatinassociated factor that is highly expressed in the brain (1, 2). Loss-of-function mutations in MeCP2 lead to the severe pediatric neurological disorder, Rett syndrome (RTT) (3), which affects around one in 10,000 girls. In addition, extra copies of the gene cause MeCP2 duplication syndrome (4, 5), a distinct intellectual disability disorder that predominantly affects males (6). The importance of MeCP2 for brain function has prompted investigation of its molecular function. The protein was identified because of its ability to bind DNA via its methyl-CpG-binding domain (MBD) (1, 7) and many residues mutated in RTT disrupt this interaction (8-11). In addition to DNA, numerous protein partners of MeCP2 have been reported (11). Of these protein partners, only the interactions with the nuclear receptor corepressor (NCoR) and its close relative silencing mediator of retinoic acid and thyroid receptors (SMRT) (12-14) are known to be disrupted by RTT missense mutations (13). Accordingly, Rett missense mutations outside the MBD are found clustered within the so-called "NCoR/SMRT interaction domain" (NID) (13) (Fig. 1A and Fig. S1A). One NID mutation, R306C, causes a severe RTT-like phenotype in mice (13,15,16). Moreover, mouse models of MeCP2 duplication syndrome suggest that both the MBD and the NID must be intact for this adverse molecular pathology to develop (16,17).These findings indicate that the NID mediates an essential function of MeCP2. This function may be recruitment of the NCoR/ SMRT corepressor complexes to chromatin. Alternatively, the NID may perform other essential roles, such as DNA binding, whose loss leads to RTT (16). In an attempt to distinguish among these possibilities, we investigated the molecular basis of the interaction between MeCP2 and NCoR/SMRT. The latter are ∼1.2-MDa multisubunit complexes that include NCoR1 (and/or SMRT), HDAC3, GPS2, and...

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Section: Mecp2supporting

confidence: 53%

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Kruusvee

Lyst

Taylor

et al. 2017

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

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“…13 The solvent-accessible area for each residue in both FXI and FXIa structures was calculated using the SURFV program with a probe sphere with a radius of 1.4Å and default parameters. 14 Evolutionary conservation analysis was performed using the ConSurf web-server 15 (http://consurf.tau.ac.il). The calculations for the serine protease domain were carried out using the …”

Section: Structural Analysis Of Mutantsmentioning

confidence: 99%

Characterization of seven novel mutations causing factor XI deficiency

Zucker¹,

Zivelin²,

Landau³

et al. 2007

Haematologica

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“…ConSurf (Armon et al 2001, Glaser et al 2003, Landau et al 2005) (http://consurf.tau.ac.il) was used to determine evolutionary conserved residues that are likely to be important for protein structure and function.…”

Section: Sequence and Phylogenetic Analysismentioning

confidence: 99%

AMP-forming acetyl-CoA synthetases in Archaea show unexpected diversity in substrate utilization

Ingram‐Smith

Smith

2006

Archaea

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Summary Adenosine monophosphate (AMP)-forming acetyl-CoA synthetase (ACS; acetate:CoA ligase (AMP-forming), EC 6.2.1.1) is a key enzyme for conversion of acetate to acetyl-CoA, an essential intermediate at the junction of anabolic and catabolic pathways. Phylogenetic analysis of putative short and medium chain acyl-CoA synthetase sequences indicates that the ACSs form a distinct clade from other acyl-CoA synthetases. Within this clade, the archaeal ACSs are not monophyletic and fall into three groups composed of both bacterial and archaeal sequences. Kinetic analysis of two archaeal enzymes, an ACS from Methanothermobacter thermautotrophicus (designated as MT-ACS1) and an ACS from Archaeoglobus fulgidus (designated as AF-ACS2), revealed that these enzymes have very different properties. MT-ACS1 has nearly 11-fold higher affinity and 14-fold higher catalytic efficiency with acetate than with propionate, a property shared by most ACSs. However, AF-ACS2 has only 2.3-fold higher affinity and catalytic efficiency with acetate than with propionate. This enzyme has an affinity for propionate that is almost identical to that of MT-ACS1 for acetate and nearly tenfold higher than the affinity of MT-ACS1 for propionate. Furthermore, MT-ACS1 is limited to acetate and propionate as acyl substrates, whereas AF-ACS2 can also utilize longer straight and branched chain acyl substrates. Phylogenetic analysis, sequence alignment and structural modeling suggest a molecular basis for the altered substrate preference and expanded substrate range of AF-ACS2 versus MT-ACS1.

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ConSurf 2005: the projection of evolutionary conservation scores of residues on protein structures

Cited by 1,276 publications

References 27 publications

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Characterization of seven novel mutations causing factor XI deficiency

AMP-forming acetyl-CoA synthetases in Archaea show unexpected diversity in substrate utilization

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