The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
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The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
The Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomet of Molecular Biophysics & Biochemistry 266 Whitney Avenue. Yale University PO Box 208114. Nev*/ Haven, CT 06520 (203) 432-6105, FAX (203) 432-5175 Mark.Gerstein@yale.edu(Version ff225rev sent to the Journal of Molecular Biology)1https://khothuvien.cori!ABSTRACTFor most proteins in the genome datab The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomeases, function is predicted via sequence comparison. In spite of the popularity of this approach, the extent to which it can be reliably applied is unThe Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
known. We address this issue by systematically investigating the relationship between protein function and structure. We focus initially on enzymes clThe Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomesses have different propensities to carry out certain broad categories of functions. For instance, alpha/beta folds are disproportionately associated with enzymes, especially transferases and hydrolases, and all-alpha and small folds with non-enzymes, while alpha-beta folds have an equal tendency ei The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomether way. These observations for the database overall are largely true for specific genomes. We focus, in particular, on yeast, analyzing it with manyThe Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
classifications in addition to SCOP and EC (i.e. COGs, CATH, MIPS), and find clear tendencies for fold-function association, across a broad spectrum The Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomestructural classes than those of more modem ones. For the database overall, we identify both most versatile functions, i.e. those that are associated with the most folds, and most versatile folds, associated with the most functions. The two most versatile enzymatic functions (hydro-1 vases and O-gly The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomecosyl glucosidases) are associated with 7 folds each. The five most versatile folds (TIM-barrel, Rossmann, ferredoxin, alpha-beta hydrolase, and P-looThe Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
p NTP hydrolase) are all mixed alpha-beta structures. They stand our as generic scaffolds, accommodating from 6 to as many as 16 functions (for the exThe Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomely transferred at different degrees of sequence and structural similarity. Supplemental information is available from http://bioinfo.mbb.yale.edu/genome/foldfunc.2INTRODUCTIONThe Problem of Determining Function from SequenceAn ultimate goal of genome analysis is to determine the biologic al (unction The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome OÍ all the gene products in a genome. However, the I unction OÍ only a minor traction of proteins has been studied experimentally, and, typically, prThe Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
ediction ol function is based on sequence similarity with proteins of known function. Thai is, functional annotation is transferred based on similaritThe Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomeerous reviews (Bork & Koonin. 1998; Katp. 1998). Karp (1998), in particular, has noted that transferring of incorrect functional infomiation threatens to progressively corrupt genome databases through the problem of accumulating incorrect annotations and using them as a basis for further annotations The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome and so on.ft is known thal sequence similarity does confer structural similarity. Moreover, there is a well-established quantitative relationship betThe Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
ween the extent of similarity in sequence and that in structure. First investigated by Chochia & Lesk, the similarity between the structures of two prThe Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome sequences are declared related, based on a database search by programs such as BLAS I' or FastA (Altschul et al., 1997; Pearson. 1996). Often, the only common element in two distantly related protein sequences is their underlying structures, or folds.Transitivity requires that the well-established The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomerelationship between sequence and structure and the more indefinite one between sequence and function imply an indefinite relationship between structuThe Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
re and function. Several recent papers have highlighted this, analyzing individual protein superfamilies with a single fold but diverse functions. ExaThe Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomeystallins, a remarkable example of functional divergence (Bork & Eisenberg, 1998; Bork er al., 1994; Cooper er al., 1993; Koonin & Tatusov, 1994; beery er al., 1998).There are also many classic examples of the converse: the same function achieved by proteins with completely different folds. For inst The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomeance, even though mammalian chymotrypsin and bacterial subtilisin have different folds, they both lunclion as serine proleases and have the same Ser-AThe Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
sp-His catalytic triad. Other examples include sugar kinases, anti-freeze glycoproteins, and lysyl-tRNA synthetases (Bork el al., 1993; Chen el al., 1The Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomedifferent function (divcigcnt evolution) and same function but different fold (convergent evolution).Protein Classification SystemsThe rapid growth in the number of prolein sequences and 3D structures has made it practical and advantageous to classify proteins into families and more elaborate hierar The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomechical systems. Proteins3are grouped together on the basis of structural similarities in the FSSP, (Holm & Sander. 1998) CATH (Orengo Ct al., 1997), aThe Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
nd SCOP databases (Murzin er al., 1995). SCOP is based on the judgments of a human expert; FSSP, on automatic methods; and CATH, on a mixture of both.The Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomed er al., 1998; Bairoch er al., 1997; Corpet er al., 1998; Fabian el al., 1997; Henikoff er al., 1998; Sonnhammer er al., 1997). Several collections contain information about proteins from a functional point of view. Some of these focus on particular organisms ■ e.g. the MIPS functional catalogue an The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomed YPD for yeast (Mewes et al., 1997; Hodges et al., 1998) and EcoCyc and GenProtEC for E. coll (Karp et al., 1998; Riley, 1997). Others focus on partiThe Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
cular functional aspects in multiple organisms. - e.g. the WIT and Kegg databases which focus on metabolism and pathways (Selkov er al., 1997; Ogata eThe Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomever phylogenetically distinct species (Tatusov et al., 1997). The ENZYME database, in particular, contains all the enzyme reactions that have an "EC number” assigned in accordance with the International Nomenclature Committee and is cross-referenced with Swissprot (Bairoch, 1996; Bairoch & Apweiler, The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome 1998; Barrett, 1997).Our approach: Systematic Comparison of Proteins Classified by Structure with those Classified by FunctionOne of the most valuablThe Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
e operations one can do to these individual classification systems is to cross-reference and cross-tabulate them, seeing how they overlap. We perform The Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome, 1995). For yeast we also have used the MIPS yeast functional catalogue, CATH, and COGs in our analysis. This enables US to investigate the relationship between protein function and structure in a comprehensive statistical fashion. In particular, we investigated the functional aspects of both diver The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomegent and convergent evolution, exploring cases where a structure gains a dramatically different biochemical function and finding instances of similarThe Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
enzymatic functions performed by unrelated structures.We concentrated on single-domain Swissprot proteins with significant sequence similarity to one The Relationship between Protein structure and Function: a Comprehensive Survey with Application to the Yeast GenomeHedi Hegyi&Mark GersteinDepartment The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomean have only one assigned fold, allowed us to establish a one-to-one relationship between structure and function.Recent Related WorkThis work is following up on several recent papers on the relationship between protein structure and function. In particular, Martin et al. studied the relationship bet The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genomeween enzyme function and the CATH fold classification (Martin el al., 1998). They concluded that functional class (expressed by top-level EC numbers)The Relationship between Protein Structure and Function a Comprehensive Survey with Application to the Yeast Genome
is not related to fold, since a few specific residues, not the whole fold, determine enzyme function. Russell also focused on specific sidechain patteGọi ngay
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