TIM barrel


  • The remaining residues are located on the loop regions that link the helices and strands; the loops at the C-terminal end of the strands tend to contain the active site, which
    is one reason this fold is so common: the residues required to maintain the structure and the residues that effect enzymatic catalysis are for the most part distinct subsets:[33] The linking loops can, in fact, be so long that they contain
    other protein domains.

  • Loop regions[edit] Of the approximately 200 residues required to fully form a TIM barrel, about 160 are considered structurally equivalent between different proteins sharing
    this fold.

  • [13] An ancestral half-barrel would have undergone a gene duplication and fusion event, resulting in a single protein containing two half-barrel domains.

  • suggested that A common phosphate binding site, formed by a small α-helix and TIM barrel loops-7/8, strongly indicated divergent evolution.

  • Structural adaptations would have occurred, resulting in the merging of these domains to form a closed β-barrel, and forming an ancestral TIM barrel.

  • The N/C-terminal and loop regions on TIM barrel proteins are capable of hosting structural inserts ranging from simple secondary structural motifs to complete domains.

  • Functional adaptations would have also occurred, resulting in the evolution of new catalytic activity at the C terminal end of the β-barrel.

  • Many TIM barrel proteins possess 2-fold, 4-fold or 8-fold internal symmetry, suggesting that TIM barrels evolved from ancestral (βα)4, (βα)2, or βα motifs through gene duplication
    and domain fusion.

  • A deep mutational scanning[31] approach and a competition assay[32] was used to determine the fitness of all possible amino acid mutants across positions in 3 hyperthermophilic
    indole-3-glycerolphosphate synthase (IGPS) TIM barrel enzymes in supporting the growth of a yeast host lacking IGPS.

  • [15][16] The crystal structure of revealed a 2-fold symmetric TIM barrel, validating the possibility of natural domain fusion.

  • All TIM barrel enzymes possess catalytic sites at the C-terminal end of the β-barrel,[25] and structural inserts present close to this end may aid in catalytic activity.

  • Chemical denaturation of several natural[27][28] and 2 designed TIM barrel variants[28] invariably involves a highly populated equilibrium intermediate.

  • In another study involving the S. solfataricus indole-3-glycerol phosphate synthase TIM barrel protein, a conserved βαβαβ module was found to be an essential folding template,
    which guided the folding of other secondary structures.

  • In some cases, structures ranging from extended loops to independent domains may be inserted in place of these loops, or may be attached to the N/C-terminals.

  • TIM barrels appear to have evolved through gene duplication and domain fusion events of half-barrel proteins,[13] with a majority of TIM barrels originating from a common

  • [10] Loops at the C-terminal ends of the β-barrel are responsible for catalytic activity[11][12] while N-terminal end loops are important for the stability of the TIM-barrels.

  • More interestingly, the loops on the C terminal ends of both HisA and HisF showed a twofold repeated pattern, suggesting that their common ancestor also possessed 2-fold internal

  • Core and pore regions[edit] TIM barrels contain two distinct buried regions, where amino acid residues are completely enveloped by their neighbors and lack access to solvent.

  • The other helices were not found to host residues critical for catalytic activity, and may serve in structural roles.

  • Structural inserts ranging from extended loops to independent protein domains may be inserted in place of these loops or at the N-terminus/C-terminals.

  • Mycobacterium tuberculosis bifunctional histidine/tryptophan biosynthesis isomerase (PDB: 2Y85) possesses the ability to catalyse two reactions: PriA is a TIM barrel enzyme
    that accommodates both substrates using active site loops (loops 1, 5, and 6, extended βα loops at the C-terminal end of the β-barrel) that change conformation depending on the reactant present.

  • Recently, it has been demonstrated that catalytic loops can be exchanged between different TIM barrel enzymes as semiautonomous units of functional groups.

  • [34] Evolution and origins The predominant theory for TIM barrel evolution involves gene duplication and fusion, starting with a half- barrel that eventually formed a full
    TIM barrel.

  • [17] These experiments led to the proposal of a novel means of diversification and evolution of TIM-barrel enzymes through the exchange of (βα)4 half-barrel domains amongst
    preexisting TIM barrels.

  • [14] Further gene duplication events of this ancestral TIM barrel led to diverging enzymes possessing the functional diversity observed today.

  • [24] Since the number of strands is equal to the shear number, side-chains point alternatively towards the pore and the core, giving a 4-fold symmetry.

  • [26] The Rossmann fold domain is colored according to secondary structural elements.

  • The design of a 4-fold symmetric TIM barrel[22] confirmed the possibility of higher orders of internal symmetry in natural TIM barrels, and will be discussed in detail in
    the next section.

  • [30] Conserved fitness landscapes[edit] TIM barrel proteins possess an unusually high sequence plasticity, forming large families of orthologous and paralogous enzymes in
    widely divergent organisms.

  • [5][6] The TIM barrel fold is evolutionarily ancient, with many of its members possessing little similarity today,[7] instead falling within the twilight zone of sequence

  • The first gene duplication resulted in two half-barrels that later fused and evolved into an ancestral TIM barrel.

  • Here, β-sheets and extended loops enclose the active site forming a cavity, while also hosting several catalytic residues.

  • The second gene duplication event lead to diversification, and the evolution of different TIM barrel enzymes catalyzing different reactions.

  • The existence of 4/8-fold internal symmetry was suggested based on a computational analysis of TIM barrel sequences.

  • The [4Fe-4S]+ center is too large to be accommodated within the TIM barrel, and is instead placed in close proximity, 7 Å away, at the interface between the TIM barrel and
    Rossmann fold domains.

  • [46] Previously-derived first principles[47] were used to delineate secondary structure topologies and lengths.

  • Four diverse examples of TIM barrels containing additional motifs and domains are discussed below.

  • Short loops typically connect the α and β secondary structures, forming a (βα)8 repeat topology.

  • These clamps (or hydrophobic side chain bridge analogs) are conserved in 3 indole-3-glycerolphosphate synthase TIM barrel orthologs from the bacterial and archaeal kingdoms,
    implying they arose in their last common ancestor and have been preserved for over a billion years.


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