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The folding and evolution of multidomain proteins

Nature Reviews Molecular Cell Biology volume 8, pages 319–330 (2007)Cite this article

Key Points

  • Multidomain proteins account for over 50% of the proteome (over 70% in eukaryotes), yet the vast majority of folding studies focus on individual domains.

  • Single-domain folding studies have identified some broad principles, however only a small fraction of the fold space has been studied. Over half of the individual domains studied have been extracted from multidomain proteins.

  • The SCOP (Structural Classification of Proteins) and SUPERFAMILY databases have been used to identify and classify domain architecture in many genomes.

  • Analysis of three-dimensional protein structures has revealed general features of the domain structure of multidomain proteins, including the extent to which domain interface geometry is conserved and the structural characteristics of domain interfaces.

  • The few multidomain-folding studies completed so far are summarized and some general features of multidomain-protein folding emerge from this limited data set: large, dense interfaces correlate with folding dependence between domains, although there are exceptions.

  • There are many mechanisms that multidomain proteins use to protect themselves from the high local domain concentrations and to avoid misfolding.

Abstract

Analyses of genomes show that more than 70% of eukaryotic proteins are composed of multiple domains. However, most studies of protein folding focus on individual domains and do not consider how interactions between domains might affect folding. Here, we address this by analysing the three-dimensional structures of multidomain proteins that have been characterized experimentally and observe that where the interface is small and loosely packed, or unstructured, the folding of the domains is independent. Furthermore, recent studies indicate that multidomain proteins have evolved mechanisms to minimize the problems of interdomain misfolding.

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Figure 1: Domain interface and folding dependency in multidomain proteins.
Figure 2: Misfolding in multidomain proteins.

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Acknowledgements

This work was funded by the Medical Research Council and the Wellcome Trust. J.C. is a Wellcome Trust Senior Research Fellow. We thank K. Levy and our colleagues in our laboratories for helpful discussions. L. Randles kindly provided Figure 2a.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

    Jung-Hoon Han & Sarah A. Teichmann

  2. University of Cambridge Department of Chemistry, MRC Centre for Protein Engineering, Lensfield Road, Cambridge, CB2 1EW, UK

    Sarah Batey, Adrian A. Nickson & Jane Clarke

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  1. Jung-Hoon Han
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Supplementary information

Supplementary information S1 (table)

Single domain proteins where the folding pathway of more than one member of a fold has been studied - including genome analysis. (PDF 364 kb)

Supplementary information S2 (table)

Multidomain proteins with experimental characterisation of folding properties (including data from Table 2) (PDF 1723 kb)

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FURTHER INFORMATION

Jane Clarke's homepage

Sarah A. Teichmann's homepage

Pfam database

Structural Classification of Proteins database

SUPERFAMILY database

Glossary

Domain

A structural, functional and evolutionary component of proteins, which can often be expressed as a single unit.

Domain interface

The surfaces of two domains where they interact with each other. In the context of this review, the two domains are part of the same polypeptide chain.

Sequence clustering

Grouping of domain families using a sequence-similarity cut-off without any structural information. So, domain sequences from the same family are more closely related to each other than to domain sequences from other families.

Family

A group of related proteins with obvious evolutionary relationships from the amino-acid sequence alone.

Superfamily

A group of related proteins that have diverged beyond recognizable sequence similarity but with clear structural evolutionary relationships.

Fold

Describes the number and the arrangement (topology) of secondary structural elements in a protein.

Sequence profile

A sequence profile represents average sequence characteristics of aligned sequences. In particular, it gives position-dependent probability for each possible amino acid as well as for insertion or deletion events at each sequence position.

All-α protein

A protein consisting entirely of α-helical structural elements.

All-β protein

A protein consisting entirely of β-sheet elements.

Contact order

A measure of the average sequence separation between contacting residues in the native state.

Chain connectivity

The N- to C-terminal order of secondary structure elements (for example, helix, strand) in a domain.

Fold space

The complete repertoire of identified folds.

Protein domain architecture

Describes the domain content of a protein in N- to C-terminal order.

Power law

One of the most frequent scaling laws that describes many natural phenomena. The relationship of the variables (for example, frequency versus number of domain partners per superfamily) following a power law can be written as y = axk. On a log–log graph, a power law is a straight line.

Local atomic density

A measure of packing density for domain interfaces. This is a measure of the average number of atoms in an interface per unit surface area.

Packing density

Packing density is the density of atoms at an interface.

Fab fragment

Fab fragments represent the forked end of an antibody, which has a Y shape. They are generated by digesting an antibody with an enzyme called papain. A Fab fragment consists of two variable (V) and two constant (C) domains. One of each type of domain comes from a light (L) and a heavy (H) chain.

Unfolding half-life

The time taken for half of the protein molecules to undergo an unfolding event — related to the unfolding rate constant. Proteins with a fast unfolding rate will have a short half-life, whereas those with a slow unfolding rate will have a long half-life.

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Han, JH., Batey, S., Nickson, A. et al. The folding and evolution of multidomain proteins. Nat Rev Mol Cell Biol 8, 319–330 (2007). https://doi.org/10.1038/nrm2144

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