Abstract
Proteins with common ancestry (homologs) typically share a common fold. This structural similarity introduces major problems for drug design since a therapeutic imperative in drug treatment is the control of specificity. As shown in this chapter, while the folding topology of the native structure is highly similar across homologs, the wrapping and expression regulation patterns tend to be different, offering an opportunity to funnel the impact of a drug solely on clinically relevant targets. The evolutionary root of the subtle dissimilarities across homologous proteins is dissected in this chapter both across species and within the human species. As anticipated in this chapter, the wrapping variations across homologs have profound consequences for drug design as we aim at engineering target-specific and species-specific therapeutic agents and build insightful animal models for disease and malignancy. In assessing the evolutionary forces that promote differences in the dehydron patterns across orthologous proteins (homologs from different species), we came across the surprising finding that random genetic drift plays a central role in causing dehydron enrichment. This type of structural degradation promotes higher protein interactivity and is more pronounced in species with low population, such as humans, where mildly deleterious mutations resulting from random drift have a higher probability of getting fixed in the population. The fitness consequences of nature’s evolutionary strategy are assessed for humans, and reveal the high exposure of the human species to fitness catastrophes resulting from aberrant protein aggregation.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Fernández A, Scott R, Berry RS (2004) The nonconserved wrapping of conserved folds reveals a trend towards increasing connectivity in proteomic networks. Proc Natl Acad Sci USA 101:2823–2827
Fernández A, Berry RS (2004) Molecular dimension explored in evolution to promote proteomic complexity. Proc Natl Acad Sci USA 101:13460–13465
Lynch M, Conery JS (2003) The origins of genome complexity. Science 302:1401–1404
Kondrashov FA, Koonin EV (2004) A common framework for understanding the origin of genetic dominance and evolutionary fates of gene duplications. Trends Genet 20:287–290
Liang H, Rogale-Plazonic K, Chen J, Li WH, Fernández A (2008) Protein under-wrapping causes dosage sensitivity and decreases gene duplicability. PLoS Genet 4:e11
Papp B, Pal C, Hurst LD (2003) Dosage sensitivity and the evolution of gene families in yeast. Nature 424:194–197
Fernández A, Scheraga H (2003) Insufficiently dehydrated hydrogen bonds as determinants for protein interactions. Proc Natl Acad Sci USA 100:113–118
Bartel D (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233
Fernández A, Chen J (2009) Human capacitance to dosage imbalance: coping with inefficient selection. Genome Res (in press)
Fernández A (2004) Keeping dry and crossing membranes. Nat Biotech 22:1081–1084
Veitia RA (2002) Exploring the etiology of haploinsufficiency. BioEssays 24:175–184
Veitia RA (2004) Gene dosage balance: deletions, duplications and dominance. Trends Genet 21:33–35
Su AI, Wiltshire T, Batalov S et al (2004) A gene atlas of the mouse and human protein-encoding transcriptomes. Proc Natl Acad Sci USA 101:6062–6067
Birney E, Andrews D, Caccamo M et al (2006) Ensembl 2006. Nucleic Acids Res 34:D556–D561
Yang Z, Nielsen R (2000) Estimating synonymous and nonsynonymous substitution rates under realistic evolutionary models. Mol Biol Evol 17:32–43
Friedman RC, Farth KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105
Lewis B, Burge C, Bartel D (2005) Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120:15–20
Grimson A, Farth KK, Johnston WK et al (2007) MicroRNA target specificity in mammals: determinants beyond seed pairing. Mol Cell 27:91–105
Aloy P, Ceulemans H, Stark A, Russell RB (2003) The relationship between sequence and interaction divergence in proteins. J Mol Biol 332:989–998
Gu Z, Nicolae D, Lu HH, Li W-H (2002) Rapid divergence in expression between duplicate genes inferred from microarray data. Trends Genet 18:609–613
Chen F, Li W-H (2001) Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am J Hum Genet 68:444–456
Gao L, Innan H (2004) Very low gene duplication rate in the yeast genome. Science 306:1367–1370
Fernández A, Lynch M (2011) Nonadaptive origins of interactome complexity. Nature 474:502–505
Ball P (2011) The Achilles’ heel of biological complexity. Nature. doi:10.1038/news.2011.294. Accessed 18 May 2011
Ball P (2011) Why are you so complex? Complicated protein interactions evolved to stave off mutations. Scientific American. http://www.scientificamerican.com/article/complicated-protein-interactions-evolved-to-stave-off-mutations/. Accessed 18 May 2011
Surmacz E, Bartucci M (2005) Role of estrogen receptor alpha in modulating IGF-I receptor signaling and function in breast cancer. J Exp Clin Cancer Res 23:385–394
Kimura M (2005) The neutral theory of molecular evolution. Cambridge University Press, Cambridge
Arnold FH, Meyerowitz JT (2014) News and views: evolving with purpose. Nature 509:166–167
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
Copyright information
© 2015 Springer International Publishing Switzerland
About this chapter
Cite this chapter
Fernández Stigliano, A. (2015). Evolution of Protein Structure Degradation and Lessons for the Drug Designer. In: Biomolecular Interfaces. Springer, Cham. https://doi.org/10.1007/978-3-319-16850-0_6
Download citation
DOI: https://doi.org/10.1007/978-3-319-16850-0_6
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-16849-4
Online ISBN: 978-3-319-16850-0
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)