βα-Hairpin Clamps Brace βαβ Modules and Can Make Substantive Contributions to the Stability of TIM Barrel Proteins

Yang, Xiao-Yan; Kathuria, Sagar V.; Vadrevu, Ramakrishna; Matthews, C. Robert

doi:10.1371/journal.pone.0007179

Cited by 17 publications

(17 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, both clamps preserve a proline at the first position of β3 and β7, and the sequence preceding both D98 and D219, GAD, is conserved. 85 This tripeptide is consistent with previous observations of a conserved GXD sequence prior to even-numbered β-strands in TIM barrel proteins. 2 …”

Section: Discussionsupporting

confidence: 92%

“…These clamps are normally formed between the NH of the amino acid in the second position from the N-terminus in an odd-numbered β-strand and, most often, the carboxylic moiety of an aspartic acid immediately preceding the subsequent even-numbered β-strand. 85 The side chains associated with the NHs in the odd-numbered β-strand are large hydrophobes, often branched aliphatic side chains, that sequester the H-bond from solvent and significantly decrease the propensity of the NH to exchange with solvent. The Class II F77–D98 H-bond clamp is found between β3/α3/β4, and the Class III I198–D219 clamp is found in the analogous position between β7/α7/β8 (Fig.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Clusters of Branched Aliphatic Side Chains Serve As Cores of Stability in the Native State of the HisF TIM Barrel Protein

Gangadhara

Laine

Kathuria

et al. 2013

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

Imidazole-3-glycerol phosphate synthase is a heterodimeric allosteric enzyme that catalyzes consecutive reactions in imidazole biosynthesis through its HisF and HisH subunits. The unusually slow unfolding reaction of the isolated HisF TIM barrel domain from the thermophilic bacteria, Thermotoga maritima, enabled an NMR-based site-specific analysis of the main-chain hydrogen bonds that stabilize its native conformation. Very strong protection against exchange with solvent deuterium in the native state was found in a subset of buried positions in α-helices and pervasively in the underlying β-strands associated with a pair of large clusters of isoleucine, leucine and valine (ILV) side chains located in the α7(βα)8(βα)1–2 and α2(βα)3–6β7 segments of the (βα)8 barrel. The most densely packed region of the large cluster, α3(βα)4–6β7, correlates closely with the core of stability previously observed in computational, protein engineering and NMR dynamics studies, demonstrating a key role for this cluster in determining the thermodynamic and structural properties of the native state of HisF. When considered with the results of previous studies where ILV clusters were found to stabilize the hydrogen-bonded networks in folding intermediates for other TIM barrel proteins, it appears that clusters of branched aliphatic side chains can serve as cores of stability across the entire folding reaction coordinate of one of the most common motifs in biology.

show abstract

Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Clusters of Branched Aliphatic Side Chains Serve As Cores of Stability in the Native State of the HisF TIM Barrel Protein

Gangadhara

Laine

Kathuria

et al. 2013

Journal of Molecular Biology

Self Cite

View full text Add to dashboard Cite

show abstract

“…Individual substitutions of Asp1 with lysine, Trp35 with alanine, and Trp42 histidine or leucine all result in poor CD spectra, indicating that all three residues are required for folding ( Supplementary Table 1 ). Incorporation of an arginine at position 21 on sTIM-1 increases the melting temperature from ~54 °C to 72 °C, perhaps due to electrostatic interactions with the helix dipoles or hydrogen bonding interactions with the α/β loop2 28 ( Supplementary Table 1 and Supplementary Fig. 4 ).…”

Section: Resultsmentioning

confidence: 99%

De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy

et al. 2015

View full text Add to dashboard Cite

Despite efforts for over 25 years, de novo protein design has not succeeded in achieving the TIM-barrel fold. Here we describe the computational design of 4-fold symmetrical (β/α)8-barrels guided by geometrical and chemical principles. Experimental characterization of 33 designs revealed the importance of sidechain-backbone hydrogen bonding for defining the strand register between repeat units. The X-ray crystal structure of a designed thermostable 184-residue protein is nearly identical with the designed TIM-barrel model. PSI-BLAST searches do not identify sequence similarities to known TIM-barrel proteins, and sensitive profile-profile searches indicate that the design sequence is distant from other naturally occurring TIM-barrel superfamilies, suggesting that Nature has only sampled a subset of the sequence space available to the TIM-barrel fold. The ability to de novo design TIM-barrels opens new possibilities for custom-made enzymes.

show abstract

“…However the numbers differ from structure to structure. This could be due to the fact that the number of correlations sampled using the percentiles changes with the size of the structure and is not a feature of the βαβ module of the structures, which has been suggested as the elementary module of the TBF [ 13 , 19 , 44 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Similarity in Shape Dictates Signature Intrinsic Dynamics Despite No Functional Conservation in TIM Barrel Enzymes

Tiwari

Reuter

2016

PLoS Comput Biol

View full text Add to dashboard Cite

The conservation of the intrinsic dynamics of proteins emerges as we attempt to understand the relationship between sequence, structure and functional conservation. We characterise the conservation of such dynamics in a case where the structure is conserved but function differs greatly. The triosephosphate isomerase barrel fold (TBF), renowned for its 8 β-strand-α-helix repeats that close to form a barrel, is one of the most diverse and abundant folds found in known protein structures. Proteins with this fold have diverse enzymatic functions spanning five of six Enzyme Commission classes, and we have picked five different superfamily candidates for our analysis using elastic network models. We find that the overall shape is a large determinant in the similarity of the intrinsic dynamics, regardless of function. In particular, the β-barrel core is highly rigid, while the α-helices that flank the β-strands have greater relative mobility, allowing for the many possibilities for placement of catalytic residues. We find that these elements correlate with each other via the loops that link them, as opposed to being directly correlated. We are also able to analyse the types of motions encoded by the normal mode vectors of the α-helices. We suggest that the global conservation of the intrinsic dynamics in the TBF contributes greatly to its success as an enzymatic scaffold both through evolution and enzyme design.

show abstract

βα-Hairpin Clamps Brace βαβ Modules and Can Make Substantive Contributions to the Stability of TIM Barrel Proteins

Cited by 17 publications

References 45 publications

Clusters of Branched Aliphatic Side Chains Serve As Cores of Stability in the Native State of the HisF TIM Barrel Protein

Clusters of Branched Aliphatic Side Chains Serve As Cores of Stability in the Native State of the HisF TIM Barrel Protein

De novo design of a four-fold symmetric TIM-barrel protein with atomic-level accuracy

Similarity in Shape Dictates Signature Intrinsic Dynamics Despite No Functional Conservation in TIM Barrel Enzymes

Contact Info

Product

Resources

About