Evolution of new protein folds

{{evolution}}
Some [[creationism| creationists]] and [[intelligent design | intelligent-design]] proponents will concede that new genetic information can arise through [[Evolution of new information |natural processes]]. However, they still claim that [[No True Scotsman | "fundamentally new"]] [[protein]]s — '''new protein folds and structures''' — cannot arise naturally.

==Principal misunderstanding==
The basic misunderstanding that this represents stems from the various problems with applying a naive interpretation of [[Darwinism]] to {{wpl|molecular evolution||.}} In essence, the argument is that it is not possible for nonfunctional proteins to exist at any stage in the evolutionary history of a particular protein in a particular [[organism]].

As our understanding of the mechanisms of genetic change increases, it becomes apparent that {{wpl|gene duplication}} is an important feature of molecular evolution. Many modern proteins are related by {{wpl|paralogous}} descent, and since duplication can free one copy from functional constraint it is free to [[mutation|mutate]] ''ad libitum''. This is one possible mechanism by which a protein could adopt a new fold. A function for the protein could arise secondarily. However, this is still an area where our knowledge is rapidly expanding.

One important observation indicates that the differences between proteins adopting different folds may be as small as a single [[amino acid]]. Cordes ''et al.'' found that the sequence of the Arc repressor protein adopts a different fold in response to the mutation of a single amino acid. A double mutant was observed to adopt either the native or the induced fold depending on the environmental conditions. The actual change is relatively small on the scale of the entire protein but involves an interchange between different secondary structural states and indicates that fold changes may occur piecewise in response to very small changes in the underlying protein sequence.<ref>[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=11101895&dopt=Citation An Evolutionary Bridge to a New Protein Fold] by M.H. Cordes et. al. (2000) ''Nat. Struct. Biol.'' 7(12):1129-132.</ref>

==Doubtful assumptions==
Further dubious assumptions implied by the argument against nonfunctional proteins are:

*'''Well-defined folding is necessary for function.''' The importance of "disordered" proteins and disordered regions of proteins is increasingly being recognized:
{{quotebox|Despite the fact that intrinsically disordered proteins fail to form fixed 3-D structure under physiological conditions, existing instead as ensembles of conformations, they carry out critically important biological functions (1,2). Several recent reviews (e.g. 3-6) attest to the growing interest in these proteins. … Conservative estimates indicate that at least 25% of the sequences in SwissProt contain long disordered regions. Similar analysis on 32 complete genomes resulted in the estimates that the percentage of proteins with long disorder in 22 [[bacteria]], 7 archaea, and 5 [[Eukaryote|eucaryotae]] ranges from 7-33%, 9-37%, and 36-63%, respectively.<ref>[https://archive.is/YRdpc DisProt — Resource for Protein Disorder], archived from the original at the Center for Computational Biology and Bioinformatics at the Indiana University School of Medicine and Center for Information Science and Technology at Temple University.</ref>}}
:Furthermore, many {{wpl|peptide}} chains that are too small to fold can exhibit important functionality.
*'''Mutating a fold always disrupts function.''' Sometimes a mutation can seriously alter the shape of a protein's fold, but with little resulting change in function. Often, only a few amino acids form the functionally important {{wpl|active site||,}} and the rest of the folded protein may simply serve as a soluble, non-degrading platform. A pathogenic form of misfolded protein is referred to as a "[[prion]]", and can cause severe brain and nerve dysfunction.
*'''Folds map to function.''' In reality, the same fold can serve many different functions (see virtually any protein superfamily), and different folds can serve the same function.<ref>[https://www.ncbi.nlm.nih.gov/Complete_Genomes/AnalEnzymes_S1.html An update to the 1998 listing of analogous enzymes.] National Center for Biotechnology Information, U.S. National Library of Medicine. Originally published in Galperin ''et. al, '' [http://www.genome.org/cgi/content/abstract/8/8/779 Analogous enzymes: Independent inventions in enzyme evolution], Genome Research, 8(8), pp. 779-790.</ref>
*'''The highly-evolved system for degrading misfolded proteins in [[eukaryote]]s tells us something meaningful about the viability of mutant folds in pre-LCA [[prokaryote]]s.''' Misfolded proteins can be disadvantageous (as a waste of resources, for example) without being fatal. Modern organisms thus may have mechanisms in place to reduce the occurrence of misfolded proteins. This would inhibit the origin or new folds in modern organisms, but the same mechanisms were not in place early in the evolution of life, when many of the new protein folds evolved.
*'''The collection of folds observed in extant life represents the universe of viable folds.''' In actually, we could be stuck with our current collection of a few thousand folds simply because they were what nature hit on first, and most of subsequent history has been operating on the "if it ain't broke, don't fix it" principle. This view seems to be confirmed by Taylor and Hou.<ref>W.R. Taylor. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11948354 A 'periodic table' for protein structures]. ''Nature'' 416(6881):657-60. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11948354 Pubmed]</ref><ref>J. Hou ''et. al,'' [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12606708 A global representation of the protein fold space.] ''PNAS'' 100(5):2386-90. [http://www.pnas.org/cgi/content/full/100/5/2386 ''PNAS'' Free Full-Text].</ref>
:Studies at at the University of California, Berkeley, and Lawrence Berkeley National Laboratory found that the protein folds observed in life are non-randomly clustered within the space of all possible protein folds.<ref>Robert Sanders, [http://www.berkeley.edu/news/media/releases/2003/02/18_table.shtml "Periodic Table" of proteins helps make sense of structure]. University of California, Berkeley, 18 February 2003.</ref>
:However, it also seems to be the case that the universe of possible folds, or at least possible folds that are relatively easily hit on by chance, is fairly small (on the order of 10<sup>4</sup>). The first artificially evolved protein fold, a zinc-binding fold, was initially thought to be novel<ref>A.D. Keefe and J.W. Szostak, [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&cmd=Retrieve&db=PubMed&list_uids=11287961&dopt=Abstract Functional proteins from a random-sequence library] Nature 410, 715-8, 2001.</ref> but was later shown to fit within a known biological fold, and is thus a clear case of analogy.<ref>S.S. Krishna and N.V. Grishin, [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15242587 Structurally analogous proteins do exist!] Structure 12, 1125-7, 2004.</ref>

Protein structure has traditionally been studied with techniques such as {{wpl|x-ray crystallography|.}} Proteins that are soluble, and have stable folds, are amenable to crystallization and therefore study through crystallography. Vast amounts of important work on proteins has been done with this method. However, many common, biologically-important proteins (such as membrane-embedded proteins and "molten globules") are difficult or impossible to crystallize.

Thus, making generalizations about proteins, based largely on methods that work best on the subset of proteins that are soluble and have regular folds, is a bit like the person who looks for his keys under the street light because that's the only place visible.

==Further reading==
*Keefe, A. D. & Szostak, J. W. (2001) "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?holding=npg&cmd=Retrieve&db=PubMed&list_uids=11287961&dopt=Abstract Functional proteins from a random-sequence library]." ''Nature'' 410, 715-8.).
*Krishna, S. S. & Grishin, N. V. 2004). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15242587 Structurally analogous proteins do exist]!" ''Structure (Camb)'' 12, 1125-7.
*Sri Krishna S, Grishin NV. (2004). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15604105 Structural drift: a possible path to protein fold change]." ''Bioinformatics''. Dec. 16, 2004. [Epub ahead of print]
*Newlove T, Konieczka JH, Cordes MH. (2004). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15062080 Secondary structure switching in Cro protein evolution]." ''Structure'' (Camb). 12(4):569-81.

{{quotebox|There are about 800 known protein topologies or "folds" (Murzin et al., 1995; Orengo et al., 1997). In principle, all of these folds could have independent evolutionary origins. More likely, some if not many of the known protein folds arose via evolutionary modifications of preexisting structures. In fact, recent reviews (Grishin, 2001; Kinch and Grishin, 2002; Murzin, 1998) have cataloged a variety of structural changes occurring in protein fold evolution, including insertion, deletion, substitution, and rearrangement of secondary structure elements. These examples show that dramatic structural changes in evolution are neither rare nor restricted to a few specific categories.}}

*Murzin AG. (1998). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=9666335 How far divergent evolution goes in proteins]." ''Curr Opin Struct Biol''. 8(3):380-7.
*Kinch LN, Grishin NV. (2002). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12127461&dopt=Abstract Evolution of protein structures and functions]." ''Curr Opin Struct Biol''. 12(3):400-8.
*Lauber T, Schulz A, Schweimer K, Adermann K, Marx UC. (2003). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12684009 Homologous proteins with different folds: the three-dimensional structures of domains 1 and 6 of the multiple Kazal-type inhibitor LEKTI]." ''J Mol Biol''. 328(1):205-19.
*Grishin NV. (2001). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11551177 Fold change in evolution of protein structures]." ''J Struct Biol''. 134(2-3):167-85.
*Cordes, M.H., Walsh, N.P., McKnight, C.J., and Sauer, R.T. (1999). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10195898 Evolution of a protein fold in vitro]." ''Science'' 284, 325â€“328. [http://www.sciencemag.org/cgi/content/full/284/5412/325 Journal] [http://dx.doi.org/10.1126/science.284.5412.325 DOI] [http://strategic.partners.org/BWH/publications/Cordes_1999_Science.pdf Free online]
*Cordes, M.H., Burton, R.E., Walsh, N.P., McKnight, C.J., and Sauer, R.T. (2000). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11101895 An evolutionary bridge to a new protein fold]." ''Nat. Struct. Biol.'' 7, 1129â€“1132. [http://strategic.partners.org/BWH/publications/Cordes_2000_NSB.pdf Free online].
*Gough J. (2005). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15585523 Convergent evolution of domain architectures (is rare)]." ''Bioinformatics'', 21(8):1464-1471. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15585523 PubMed] [http://dx.doi.org/10.1093/bioinformatics/bti204 DOI]
*Whitman CP. (2002). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12051677 The 4-oxalocrotonate tautomerase family of enzymes: how nature makes new enzymes using a beta-alpha-beta structural motif]." ''Arch Biochem Biophys''. 402(1):1-13.[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12051677 PubMed] [http://dx.doi.org/10.1016/S0003-9861(02)00052-8 DOI]
*Almrud JJ, Kern AD, Wang SC, Czerwinski RM, Johnson WH Jr, Murzin AG, Hackert ML, Whitman CP. (2002). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12356301 The crystal structure of YdcE, a 4-oxalocrotonate tautomerase homologue from Escherichia coli, confirms the structural basis for oligomer diversity]." ''Biochemistry''. 41(40):12010-24. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12356301 PubMed].
*Ballicora MA, Dubay JR, Devillers CH, Preiss J. (2005). "[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15632142 Resurrecting the ancestral enzymatic role of a modulatory subunit]." ''J Biol Chem.'' 280(11):10189-95. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15632142 PubMed]

==References==
{{reflist|2|80%}}

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