Point Mutations in Protein Globular Domains: Contributions from Function, Stability and Misfolding

Sánchez, Ignacio E.; Tejero, Jesús; Gómez‐Moreno, Carlos; Medina, Milagros; Serrano, Luís

doi:10.1016/j.jmb.2006.08.020

Cited by 42 publications

(60 citation statements)

References 78 publications

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“…13 and Methods). For simplicity, we assume that the probability distribution W is the same for all proteins, because it is a statistical property directly following from the physics of interactions among amino acid residues in the protein structure.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Protein stability imposes limits on organism complexity and speed of molecular evolution

Zeldovich¹,

Chen

Shakhnovich³

2007

Proc. Natl. Acad. Sci. U.S.A.

250

324

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Classical population genetics a priori assigns fitness to alleles without considering molecular or functional properties of proteins that these alleles encode. Here we study population dynamics in a model where fitness can be inferred from physical properties of proteins under a physiological assumption that loss of stability of any protein encoded by an essential gene confers a lethal phenotype. Accumulation of mutations in organisms containing ⌫ genes can then be represented as diffusion within the ⌫-dimensional hypercube with adsorbing boundaries determined, in each dimension, by loss of a protein's stability and, at higher stability, by lack of protein sequences. Solving the diffusion equation whose parameters are derived from the data on point mutations in proteins, we determine a universal distribution of protein stabilities, in agreement with existing data. The theory provides a fundamental relation between mutation rate, maximal genome size, and thermodynamic response of proteins to point mutations. It establishes a universal speed limit on rate of molecular evolution by predicting that populations go extinct (via lethal mutagenesis) when mutation rate exceeds approximately six mutations per essential part of genome per replication for mesophilic organisms and one to two mutations per genome per replication for thermophilic ones. Several RNA viruses function close to the evolutionary speed limit, whereas error correction mechanisms used by DNA viruses and nonmutant strains of bacteria featuring various genome lengths and mutation rates have brought these organisms universally Ϸ1,000-fold below the natural speed limit. biological evolution ͉ genome sizes ͉ lethal mutagenesis ͉ mutation load ͉ population genetics

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Section: Resultsmentioning

confidence: 99%

“…The analysis of the data on point mutations available in the ProTherm database (18) and in ref. 13 gives h ϭ 1(kcal/mol); D Ϸ 3(kcal/mol) 2 (see Methods and SI Text). In the diffusion approximation, Eqs.…”

Section: Resultsmentioning

confidence: 99%

Protein stability imposes limits on organism complexity and speed of molecular evolution

Zeldovich¹,

Chen

Shakhnovich³

2007

Proc. Natl. Acad. Sci. U.S.A.

250

324

View full text Add to dashboard Cite

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“…For example, we find that nearly half [44% (1139 of 2615); Dataset S1] of the variants annotated in the PMD as functionally neutral and evaluated for structural changes have been shown by experiments cited in the PMD to affect protein structure/stability. Because structural disturbance often changes function (16), these, and likely other, annotations of functional neutrality require deeper exploration. Moreover, the shape and position of the PMDneutral distribution suggests a set of weakly disruptive variants, closer to the PMDmilds (Fig.…”

Section: Resultsmentioning

confidence: 99%

Neutral and weakly nonneutral sequence variants may define individuality

Bromberg

Kahn

Rost

2013

Proc. Natl. Acad. Sci. U.S.A.

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Large-scale computational analyses of the growing wealth of genome-variation data consistently tell two distinct stories. The first is expected: coding variants reported in disease-related databases significantly alter the function of affected proteins. The second is surprising: the genomes of healthy individuals appear to carry many variants that are predicted to have some effect on function. As long as the complete experimental analysis of all human genome variants remains impossible, computational methods, such as PolyPhen, SNAP, and SIFT, might provide important insights. These methods capture the effects of particular variants very well and can highlight trends in populations of variants. Diseases are, arguably, extreme phenotypic variations and are often attributable to one or a few severely functionally disruptive variants. Our findings suggest a genomic basis of the different nondisease phenotypes. Prediction methods indicate that variants in seemingly healthy individuals tend to be neutral or weakly disruptive for protein molecular function. These variant effects are predicted to be largely either experimentally undetectable or are not deemed significant enough to be published. This may suggest that nondisease phenotypes arise through combinations of many variants whose effects are weakly nonneutral (damaging or enhancing) to the molecular protein function but fall within the wild-type range of overall physiological function.nsSNP | coding SNV | variome analysis | genomic variant burden | evolution

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“…As mentioned, active sites are flexible, primed for substrate recognition and rate enhancement, and so sacrifice the stability ethos of the remaining protein scaffold (44,45). Mutations such as F283L, introducing greater flexibility within this region, may destabilize the enzyme by increasing active site strain or loss of favorable interactions (42) (Fig.…”

Section: Discussionmentioning

confidence: 99%

Evolution toward Small Molecule Inhibitor Resistance Affects Native Enzyme Function and Stability, Generating Acarbose-insensitive Cyclodextrin Glucanotransferase Variants

Kelly

Leemhuis

Gätjen

et al. 2008

Journal of Biological Chemistry

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Small molecule inhibitors play an essential role in the selective inhibition of enzymes associated with human infection and metabolic disorders. Targeted enzymes may evolve toward inhibitor resistance through selective incorporation of mutations. Acquisition of insensitivity may, however, result in profound devolution of native enzyme function and stability. We therefore investigated the consequential effects on native function and stability by evolving a cyclodextrin glucanotransferase (CGTase) enzyme toward insensitivity to the small molecule inhibitor of the protein, acarbose. Errorprone PCR mutagenesis was applied to search the sequence space of CGTase for acarbose-insensitive variants. Our results show that all selected mutations were localized around the active site of the enzyme, and in particular, at the acceptor substrate binding sites, highlighting the regions importance in acarbose inhibition. Single mutations conferring increased resistance, K232E, F283L, and A230V, raised IC 50 values for acarbose between 3,500-and 6,700-fold when compared with wild-type CGTase but at a significant cost to catalytic efficiency. In addition, the thermostability of these variants was significantly lowered. These results reveal not only the relative ease by which resistance may be acquired to small molecule inhibitors but also the considerable cost incurred to native enzyme function and stability, highlighting the subsequent constraints in the further evolutionary potential of inhibitor-resistant variants.

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Point Mutations in Protein Globular Domains: Contributions from Function, Stability and Misfolding

Cited by 42 publications

References 78 publications

Protein stability imposes limits on organism complexity and speed of molecular evolution

Protein stability imposes limits on organism complexity and speed of molecular evolution

Neutral and weakly nonneutral sequence variants may define individuality

Evolution toward Small Molecule Inhibitor Resistance Affects Native Enzyme Function and Stability, Generating Acarbose-insensitive Cyclodextrin Glucanotransferase Variants

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