Trends in Biochemical Sciences
Conformational diversity and protein evolution – a 60-year-old hypothesis revisited
Section snippets
The ‘new view’ of protein function
Traditionally, it is assumed that a given sequence dictates a single 3D structure upon which function is entirely dependent. This view is manifested in the ‘lock-and-key’ and ‘induced-fit’ models of action, in which the structure is entirely fixed or changes (locally, around the active site) only after a ligand is bound (Box 1). Both models are strongly supported by the principal method used to study protein structure – X-ray crystallography. However, crystallization is, by definition, a
Linking conformational diversity and functional diversity
An intriguing consequence of conformational diversity is that it provides a mechanism for functional diversity at the single-protein level. A protein that adopts several different conformations could, in principle, exert several different functions [20]. A significant number of proteins that exhibit multiple activities have been identified 21, 22 but the mechanism behind this promiscuity or cross-reactivity, in most cases, involves the same active-site configuration that confers the original
Conformational diversity and protein evolution
In the 1930s, Landsteiner and Pauling 44, 45 proposed that proteins (antibodies in this case) can exist as an ensemble of isomers with different structures but with similar free energy. They realized that if each isomer was capable of binding to a different ligand, then functional diversity could go far beyond sequence diversity (Box 2). This idea, although considered outlandish for many decades, now proves to be remarkably prescient of the ‘new view’ of proteins. It also has intriguing
The co-evolution of fold and function
The proposed model (Box 3) describes how existing genes could diverge to evolve new functions, but it can also be extended to explain how primordial protein precursors evolved in the first place. The emergence of the first functional proteins is a complete mystery. It is generally assumed that proteins exert function only when folded into a well-defined 3D structure. However, fold alone provides no selective advantage and, thus, cannot evolve independently. We are therefore left with an
Concluding remarks
The ‘new view’ of proteins has prompted the revision of many facets of protein science. Here, we have outlined the intriguing implications that this ‘new view’ might have for protein evolution. The hypotheses described are supported by many properties of today's proteins, including the recent demonstration of a linkage between conformational diversity and multi-specificity in antibodies [16] (Fig. 2). Moreover, although present-day enzymes do not necessarily retain the activities of their
Acknowledgements
Financial support by the Wellcome Trust, the EU (through the ENDIRPRO network) and the Israel Science Foundation is gratefully acknowledged.
Glossary
Glossary
- Numerous terms exist that describe the ability of a single protein to exhibit more than one specificity or perform more than one function. These terms are not necessarily distinct and are, in many senses, overlapping; they are often used in parallel or in a different context than described herein. Here, we attempt to define a clearer terminology and distinct uses for these terms. A detailed discussion of promiscuity, moonlighting and cross-reactivity can be found in Ref. [22].
- Conformational
References (48)
Conformational changes affect binding and catalysis by ester-hydrolysing antibodies
J Mol Biol
(1999)- et al.
Calculation of ensembles of structures representing the unfolded state of an SH3 domain
J. Mol. Biol.
(2001) Evidence that the 127–164 region of prion proteins has two equi-energetic conformations with β or α features
Biophys. J.
(2001)- et al.
Intrinsically unstructured proteins: re-assessing the protein structure–function paradigm
J. Mol. Biol.
(1999) Intrinsically unstructured proteins
Trends Biochem. Sci.
(2002)- et al.
Equilibrium and rate constants for the interconversion of two conformations of chymotrypsin. The existence of a catalytically inactive conformation at neutral pH
J. Mol. Biol.
(1971) - et al.
Catalytic promiscuity and the evolution of new enzymatic activities
Chem. Biol.
(1999) The crystal structure and mode of action of trans-sialidase, a key enzyme in Trypanosoma cruzi pathogenesis
Mol. Cell
(2002)- et al.
The trypanosomal trans-sialidase: two catalytic functions associated with one catalytic site
Structure
(2002) - et al.
Man-made enzymes – from design to in vitro compartmentalisation
Curr. Opin. Biotechnol.
(2000)
Moonlighting proteins
Trends Biochem. Sci.
In vitro evolution of β-glucuronidase into a β-galactosidase proceeds through non-specific intermediates
J. Mol. Biol.
Antibody framework residues affecting the conformation of the hypervariable loops
J. Mol. Biol.
Direct structural evidence for a concerted allosteric transition in Escherichia coli aspartate transcarbamoylase
Nat. Struct. Biol.
Two-state allosteric behavior in a single-domain signaling protein
Science
An evolutionary bridge to a new protein fold
Nat. Struct. Biol.
Conformational diversity in a yeast prion dictates its seeding specificity
Nature
Natively unfolded proteins: a point where biology waits for physics
Protein Sci.
Multiple conformational changes in enzyme catalysis
Biochemistry
Dynamic properties of the Ras switch I region and its importance for binding to effectors
Proc. Natl. Acad. Sci. U. S. A.
Flexibility, conformational diversity and two dimerization modes in complexes of ribosomal protein L12
EMBO J.
Kinetic evidence for hapten-induced conformational transition in immunoglobin MOPC 460
Proc. Natl. Acad. Sci. U. S. A.
Antibody multi-specificity mediated by conformational diversity
Science
Structure and dynamics of the α-lactalbumin molten globule: fluorescence studies using proteins containing a single tryptophan residue
Biochemistry
Cited by (493)
An optimized purification protocol for enzymatically synthesized S-adenosyl-L-methionine (SAM) for applications in solution state infrared spectroscopic studies
2024, Spectrochimica Acta - Part A: Molecular and Biomolecular SpectroscopyMD simulations indicate Omicron P132H of SARS-CoV-2 M<sup>pro</sup> is a potential allosteric mutant involved in modulating the dynamics of catalytic site entry loop
2024, International Journal of Biological MacromoleculesIdentical sequences, different behaviors: Protein diversity captured at the single-molecule level
2024, Biophysical JournalExperimentally Observed Conformational Changes in Antibodies Due to Binding and Paratope-epitope Asymmetries
2023, Journal of Pharmaceutical SciencesSubstrate-dependent inactivation of recombinant paraoxonase 1 during catalytic dihydrocoumarin turnover and the protective properties of surfactants
2023, Chemico-Biological InteractionsRole of distal sites in enzyme engineering
2023, Biotechnology Advances