Are proteins made of modules?

Traut, Thomas W.

doi:10.1007/bf00233799

Cited by 18 publications

(6 citation statements)

References 64 publications

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“…Contemporary enzymes the size of aaRS Urzymes exist, but they are hydrolases and isomerases that act on a single substrate; multisubstrate enzymes generally have considerably more mass [ 39 ]. The average modular molecular weight of 5000 Kd/ligand from a survey of molecular mass required per ligand bound [ 40 ] suggests a minimum molecular mass of 20 Kd for such enzymes. In fact, enzymes that bind nucleotide ligands from that survey have a mean molecular mass of 41 Kd with a standard error of the mean of 1.9 Kd.…”

Section: Resultsmentioning

confidence: 99%

What RNA World? Why a Peptide/RNA Partnership Merits Renewed Experimental Attention

Carter

2015

Life

128

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We review arguments that biology emerged from a reciprocal partnership in which small ancestral oligopeptides and oligonucleotides initially both contributed rudimentary information coding and catalytic rate accelerations, and that the superior information-bearing qualities of RNA and the superior catalytic potential of proteins emerged from such complexes only with the gradual invention of the genetic code. A coherent structural basis for that scenario was articulated nearly a decade before the demonstration of catalytic RNA. Parallel hierarchical catalytic repertoires for increasingly highly conserved sequences from the two synthetase classes now increase the likelihood that they arose as translation products from opposite strands of a single gene. Sense/antisense coding affords a new bioinformatic metric for phylogenetic relationships much more distant than can be reconstructed from multiple sequence alignments of a single superfamily. Evidence for distinct coding properties in tRNA acceptor stems and anticodons, and experimental demonstration that the two synthetase family ATP binding sites can indeed be coded by opposite strands of the same gene supplement these biochemical and bioinformatic data, establishing a solid basis for key intermediates on a path from simple, stereochemically coded, reciprocally catalytic peptide/RNA complexes through the earliest peptide catalysts to contemporary aminoacyl-tRNA synthetases. That scenario documents a path to increasing complexity that obviates the need for a single polymer to act both catalytically and as an informational molecule.

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Section: Resultsmentioning

confidence: 99%

What RNA World? Why a Peptide/RNA Partnership Merits Renewed Experimental Attention

Carter

2015

Life

128

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“…Such a structure would be an excellent scaffold for fixing interactive side chains. Indeed it is now generally recognized that modules are fundamentally and autonomously folding units of large proteins, and one reason for the evolution of modules is to endow proteins with ligand binding capacity (45)(46)(47). The observation that the FIMs are facilitating devices that promote interaction of C5 and C6, which is important for antibody-mediated complement activation, conveys implications as to how the terminal pathway of complement evolved.…”

Section: Fig 10 the Affinity Of C5 For C6mentioning

confidence: 99%

Function of the Factor I Modules (FIMS) of Human Complement Component C6

DiScipio¹,

Linton²,

Rushmere³

1999

Journal of Biological Chemistry

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In order to elucidate the function of complement component C6, truncated C6 molecules were expressed recombinantly. These were either deleted of the factor I modules (FIMs) (C6des-748 -913) or both complement control protein (CCP) modules and FIMs (C6des-611-913). C6des-748 -913 exhibited approximately 60 -70% of the hemolytic activity of full-length C6 when assayed for Alternative Pathway activity, but when measured for the Classical Pathway, C6des-748 -914 was only 4 -6% as effective as C6. The activity difference between C6 and C6des-748 -913 for the two complement pathways can be explained by a greater stability of newly formed metastable C5b* when produced by the Alternative Pathway compared with that made by the Classical Pathway. The half-lives of metastable C5b* and the decay of 125 I-C5b measured from cells used to activate the Alternative Pathway were found to be about 5-12-fold longer than those same parameters derived from cells that had activated the Classical Pathway.125 I-C5 binds reversibly to C6 in an ionic strength-dependent fashion, but 125 I-C5 binds only weakly to C6des-FIMs and not at all to C6des-CCP/FIMs. Therefore, although the FIMs are not required absolutely for C6 activity, these modules promote interaction of C6 with C5 enabling a more efficient bimolecular coupling ultimately leading to the formation of the C5b-6 complex.Human complement component C6 is a plasma protein of M r ϭ 104,000, which consists of 913 amino acids and two asparaginyl-linked oligosaccharide side chains (1, 2). The protein is a composite containing several discrete modules homologous to those found in thrombospondin, the low density lipoprotein receptor, the epidermal growth factor, factor H, and factor I. The protein also has regional homology with complement C9 and a more restricted homology with the T-lymphocyte granular protein, perforin (1, 2).The function of C6 is to link with C5b in order to form the C5b-6 complex (3, 4). This coupling entails an interaction of C6 with a metastable intermediate of the activated fifth component of complement, designated here as C5b*. After C5 is cleaved by C5 convertase the larger fragment, C5b*, is endowed with a transient ability to form an irreversible complex with C6. If C5b* fails to bind C6 within a short period, C5b* activity decays permanently (4, 5). A further manifestation of this irreversibility is that if C5b-6 were dissociated by chaotrophs, the complex cannot reform (4).The formation of C5b-6 is the first step in the construction of the membrane attack complex (MAC), 1 which is responsible for generating transmembrane channels through target cells. The MAC has the structure of a phospholipid membrane-embedded tubule having a leaflet projecting from within the interior wall. The MAC in its complete state creates a stable circular transmembrane channel of ϳ100 Å (for reviews on the MAC see Refs. 6 -8).How the modules and regions of C6 participate in the formation of the MAC is an ongoing topic of research. The demonstration that C6 can link with C7, C84, and C...

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“…While there is insufficient data to relate the various motifs described here with exons in their genes, it has been stated that Walker A and B segments should be independently folding domains [52], which is consistent with considering them as protein modules. The benefits of such modular architecture have been more specifically described for enzymes, where the functional benefit of using two modules for a ligand-binding pocket were considered [47,481. If the motifs described here for binding ATPIGTP and NMP correspond to modules, then this would give examples for slightly more complex ligand-binding sites.…”

Section: Motifs and Modulesmentioning

confidence: 99%

The functions and consensus motifs of nine types of peptide segments that form different types of nucleotide‐binding sites

Traut

1994

European Journal of Biochemistry

354

216

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From an analysis of current data on 16 protein structures with defined nucleotide-binding sites consensus motifs were determined for the peptide segments that form such nucleotide-binding sites. This was done by using the actual residues shown to contact ligands in the different protein structures, plus an additional 50 sequences for various kinases. Three peptide segments are commonly required to form the binding site for ATP or GTP. Binding motif Kinase-1 a is found in almost all sequences examined, and functions in binding the phosphates of the ligand. Variant versions, comparable to Kinase-1 a, are found in a subset of proteins and appear to be related to unique functions of those enzymes. Motif Kinase-2 contains the conserved aspartate that coordinates the metal ion on Mg-ATP. Motif Kinase-3 occurs in at least four versions, and functions in binding the purine base or the pentose. Two protein structures show ATP-binding at a separate regulatory site, formed by the motifs Regulatory-1 and Regulatory-2. Structures for adenylate kinase and guanylate kinase show three different sequence motifs that form the binding site for a nucleoside monophosphate (NMP). NMP-I and NMP-2 bind to the pentose and phosphate of the bound ligand. NMP-I is found in almost all the kinases that phosphorylate AMP, CMP, GMP, dTMP, or UMP. NMP-3a is found in kinases for AMP, GMP, and UMP, while NMP-3b binds only GMP. For the binding of NTPs, three distinct types of nucleotide-binding fold structures have been described. Each structure is associated with a particular function (e.g. transfer of the y-phosphate, or of the adenylate to an acceptor) and also with a particular spatial arrangement of the three Kinase segments evident in the linear sequence for the protein.With the rapid proliferation of DNA sequences in the last decade, the finding that a few consensus sequences might generally correspond to ATP-binding sites was immediately useful. In 1982 Walker et al. deduced from a search of available sequences for ATP-binding proteins that one, or both, of two sequence motifs appeared in nine proteins, with four proteins having both sequences [l]. Since both of these motifs occurred in porcine adenylate kinase, at positions corresponding to the proposed nucleotide-bindmg site in the crystal structure [2], the association of these sequences with actual ATP-bindmg appeared to be established. Although adenylate kinase uses ATP to phosphorylate AMP, the crystal structure then available had some ambiguity as to whether the Walker A site or the Walker B site bound ATP or AMP; the appearance of these motif sequences in other ATP-binding proteins favored the former nucleotide site. Since this original paper also found only a Walker B sequence in phosphofructokinase [l], an easy interpretation was that either

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Are proteins made of modules?

Cited by 18 publications

References 64 publications

What RNA World? Why a Peptide/RNA Partnership Merits Renewed Experimental Attention

What RNA World? Why a Peptide/RNA Partnership Merits Renewed Experimental Attention

Function of the Factor I Modules (FIMS) of Human Complement Component C6

The functions and consensus motifs of nine types of peptide segments that form different types of nucleotide‐binding sites

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