PSI-BLAST searches using hidden Markov models of structural repeats: prediction of an unusual sliding DNA clamp and of beta-propellers in UV-damaged DNA-binding protein

Abstract

We have designed hidden Markov models (HMMs) of structurally conserved repeats that, based on pairwise comparisons, are unconserved at the sequence level. To model secondary structure features these HMMs assign higher probabilities of transition to insert or delete states within sequence regions predicted to form loops. HMMs were optimized using a sampling procedure based on the degree of statistical uncertainty associated with parameter estimates. A PSI-BLAST search initialized using a checkpoint-recovered profile derived from simulated sequences emitted by such a HMM can reveal distant structural relationships with, in certain instances, substantially greater sensitivity than a normal PSI-BLAST search. This is illustrated using two examples involving DNA- and RNA-associated proteins with structurally conserved repeats. In the first example a putative sliding DNA clamp protein was detected in the thermophilic bacterium Thermotoga maritima. This protein appears to have arisen by way of a duplicated beta-clamp gene that then acquired features of a PCNA-like clamp, perhaps to perform a PCNA-related function in association with one or more of the many archaeal-like proteins present in this organism. In the second example, beta-propeller domains were predicted in the large subunit of UV-damaged DNA-binding protein and in related proteins, including the large subunit of cleavage-polyadenylation specificity factor, the yeast Rse1p and human SAP130 pre-mRNA splicing factors and the fission yeast Rik1p gene silencing protein.

DDB1 functions as a linker to recruit receptor WD40 proteins to CUL4–ROC1 ubiquitin ligases

“…Two obvious candidate linkers for binding with these putative DWD proteins are CPSF160 (the cleavage and polyadenylation specificity factor A, 160-kDa subunit) and SAP130 (spliceosome-associated protein 130). Both CPSF160 and SAP130 are present in budding yeast and exhibit a low-level similarity with DDB1 at the primary sequence level, but contain similar ␤-propellers, as predicted by computational modeling (Neuwald and Poleksic 2000) and reinforced by comparison with the DDB1 crystal structure ).…”

Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer

“…Although Dos1 and Dos2 show weak similarity to WD-repeat proteins and zinc finger proteins, respectively, homologs in other organisms have not been described. Instead, it has been proposed that Rik1 is structurally related to the CUL4 complex adaptor protein DDB1 (63) through its WD-propeller-repeat domains (64,65), despite limited primary sequence homology. Intriguingly, Rik1 is required during the S phase to establish heterochromatin (62, 66).…”

Conserved factor Dhp1/Rat1/Xrn2 triggers premature transcription termination and nucleates heterochromatin to promote gene silencing

“…Dhp1 may be a component of a specialized 3′ pre-mRNA processing and termination complex that directly engages the ClrC complex. In this regard, we note that the Rik1 subunit of ClrC shares sequence similarity with the cleavage and polyadenylation specificity factor (CPSF)-A protein, which functions in 3′-end processing (58). The significance of Rik1 homology to a 3′-end processing factor has remained a long-standing mystery.…”