The emergence of catalytic and structural diversity within the beta-clip fold.
The beta-clip fold includes a diverse group of protein domains that are unified by the presence of two characteristic waist-like constrictions, which bound a central extended region. Members of this fold include enzymes like deoxyuridine triphosphatase and the SET methylase, carbohydrate-binding domains like the fish antifreeze proteins/Sialate synthase C-terminal domains, and functionally enigmatic accessory subunits of urease and molybdopterin biosynthesis protein MoeA. In this study, we reconstruct the evolutionary history of this fold using sensitive sequence and structure comparisons methods. Using sequence profile searches, we identified novel versions of the beta-clip fold in the bacterial flagellar chaperone FlgA and the related pilus protein CpaB, the StrU-like dehydrogenases, and the UxaA/GarD-like hexuronate dehydratases (SAF superfamily). We present evidence that these versions of the beta-clip domain, like the related type III anti-freeze proteins and C-terminal domains of sialic acid synthases, are involved in interactions with carbohydrates. We propose that the FlgA and CpaB-like proteins mediate the assembly of bacterial flagella and Flp pili by means of their interactions with the carbohydrate moieties of peptidoglycan. The N-terminal beta-clip domain of the hexuronate dehydratases appears to have evolved a novel metal-binding site, while their C-terminal domain is likely to adopt a metal-binding TIM barrel-like fold. Using structural comparisons, we show that the beta-clip fold can be further classified into two major groups, one that includes the SAF, SET, dUTPase superfamilies, and the other that includes the phage lambda head decoration protein, the beta subunit of urease and the C-terminal domain of the molybdenum cofactor biosynthesis protein MoeA. Structural comparisons also suggest the beta-clip fold was assembled through the duplication of a three-stranded unit. Though the three-stranded units are likely to have had a common origin, we present evidence that complete beta-clip domains were assembled through such duplications, independently on multiple occasions. There is also evidence for circular permutation of the basic three-stranded unit on different occasions in the evolution of the beta-clip unit. We also describe how assembly of this fold from a basic three-stranded unit has been utilized to accommodate a variety of activities in its different versions.
Iyer
Lakshminarayan M
LM
National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, Maryland 20894, USA.
Aravind
L
L
D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D050260:Carbohydrate Metabolism; D002384:Catalysis; D019143:Evolution, Molecular; D006836:Hydro-Lyases / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000737:chemistry; D007652:Oxo-Acid-Lyases / Q000737:chemistry; D010802:Phylogeny; D017510:Protein Folding; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000502:physiology; D016415:Sequence Alignment; D020539:Sequence Analysis, Protein
D001426:Bacterial Proteins; D011506:Proteins; D010088:Oxidoreductases; C018730:N-acetylneuraminate synthase; D007652:Oxo-Acid-Lyases; D006836:Hydro-Lyases