Crystal structure of interleukin-10 reveals the functional dimer with an unexpected topological similarity to interferon γ

Abstract3D domain swapping is a mechanism for forming oligomeric proteins from their monomers. In 3D domain swapping, one domain of a monomeric protein is replaced by the same domain from an identical protein chain. The result is an intertwined dimer or higher oligomer, with one domain of each subunit replaced by the identical domain from another subunit. The swapped "domain" can be as large as an entire tertiary globular domain, or as small as an a-helix or a strand of a P-sheet. Examples of 3D domain swapping are reviewed that suggest domain swapping can serve as a mechanism for functional interconversion between monomers and oligomers, and that domain swapping may serve as a mechanism for evolution of some oligomeric proteins. Domain-swapped proteins present examples of a single protein chain folding into two distinct structures.Keywords: aggregation; complementation; oligomer evolution; protein dimerization Since Svedberg's discovery of functional molecules composed of two or more identical protein chains, much effort has been expended in studying their metabolic regulation (Monod et al., 1965;Koshland et al., 1966) and their assembly and disassembly (Kikuchi & King, 1975;Caspar, 1980;Jaenicke, 1995).Despite this progress, understanding the assembly of oligomeric proteins from monomers remains a challenge. A common observation is that disassembly of an oligomeric protein into its monomeric subunits is accompanied by irreversible unfolding and aggregation. This observation is often interpreted in terms of exposing apolar patches on the monomer surface that are covered in the oligomer, thereby providing binding energy from a hydrophobic interaction. Thus, the question remains of how the oligomer could have been assembled in the first place. We propose an answer to this question for some oligomers based on a mode of association that we have noticed in several proteins of Reprint requests to: David Eisenberg, Molecular Biology Institute, Department of Chemistry and Biochemistry, and UCLA-DOE Laboratory of Structural Biology and Molecular Medicine, University of California-Los Angeles, Los Angeles, California 90095-1570; e-mail: david@pauling.rnbi.ucla.edu.Abbreviations: BS-RNase, bovine seminal ribonuclease; DT, diphtheria toxin; GM-CSF, granulocyte-macrophage colony-stimulating factor; GST, glutathione S-transferase; IF, interferon; IL, interleukin; RNase, ribonuclease. known structure. We term this mode of association 3 0 domain swapping, because oligomers are formed from stable monomers by exchanging domains.A problem related to the formation of oligomeric proteins in a cell is the problem of how oligomeric proteins evolved from monomeric precursor proteins. For an oligomer to evolve, random mutations must change the surface of the monomer so that sufficient free energy is released upon oligomerization to overcome the accompanying entropy loss of immobilizing the monomers. As we discuss in this review, single amino acid replacements must be fortuitous to provide an adequate free energy of interaction. But an ...

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“…E Recombinant murine interferon P at 2.2 A resolution (Senda et al, 1992). F: Recombinant human 1L-10 at 1.8 A resolution (Zdanov et al, 1995).…”

Section: Two Models For Oligomer Evolutionmentioning

confidence: 99%

3D domain swapping: A mechanism for oligomer assembly

1995

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“…IL-10 structural description The crystal structure of IL-10 was the first reported three-dimensional structure of an IL-10 family member [6,7], which revealed an unexpected similarity with the IFN-c 3D fold [7]. Differently from what is observed for the IL-19 subfamily members, IL-10 forms intimate intertwined homodimers.…”

Section: Il-10mentioning

confidence: 97%

“…The crystal structures of IL-10 [6,7], IL-19 [24], IL-22 [8,25], and, more recently, IFN-k3 [23] have been determined. Based on the information extracted from these 3D structures, as well as sequence alignments and secondary structure prediction, one can draw several conclusions about IL-10 family members' secondary, tertiary, and quaternary organization.…”

Section: Three-dimensional Structure Considerationsmentioning

confidence: 99%

“…Each IL-10 subunit has two disulfide bonds connecting the DE loop to helix C (Cys62-Cys114) and to the N-terminal region (Cys12-Cys108). These S-S interactions, mainly the one between Cys62 and Cys114, promote a certain degree of rigidity of helix E. As a consequence, helices E and F fold as an independent IL-10 domain that makes a right angle with the other domain composed of helices A-D [6,7,130,131]. This promotes two IL-10 polypeptide chains to join together to form an intertwined V-shaped dimer.…”

Section: Il-10mentioning

confidence: 99%

“…These cytokines were grouped together based on sequence alignment, structural homology, and binding to shared class II cytokine receptor chains that activate the JAK/STAT pathway [2][3][4][5]. IL-10 family members are helical proteins formed by six or seven helices and connecting loops [6][7][8]. Each IL-10 member can associate with the extracellular portion of two transmembrane proteins from the class II cytokine receptor, forming a heterodimeric complex.…”

Section: Introductionmentioning

confidence: 99%

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Structure and function of interleukin-22 and other members of the interleukin-10 family

Trivella

Ferreira-Junior

Dumoutier

et al. 2010

Cell. Mol. Life Sci.

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The IL-10 family of cytokines is comprised of IL-10, . The IL-10 family members bind to shared class II cytokine receptor chains that associate in various combinations in heterodimeric complexes. Upon interleukin/receptor complex formation, these proteins switch on the Jak/STAT pathway and elicit pleiotropic biological responses whose variety sharply contrasts with their structural similarities. IL-10 family members are involved in several human diseases and health conditions and hence their structural analyses may provide valuable information to design specific therapeutic strategies. In this review, we describe the human interleukin-10 family of cytokines, focusing on their structures and functions, with particular attention given to IL-22 and IL-10. We report on the recently published structures of IL-10 cytokine family members and their complexes with cognate transmembrane and soluble receptors as well as on interleukin physiology and physiopathology.

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Evidence for conformationally different states of interleukin-10: binding of a neutralizing antibody enhances accessibility of a hidden epitope

et al. 1999

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We present the mapping of two anti-human interleukin-10 (hIL-10) antibodies (CB/RS/2 and CB/RS/11) which have been described as binding their antigen cooperatively. The epitopes were identified using hIL-10-derived overlapping peptide scans prepared by spot synthesis. To identify residues essential for binding within the two epitopes, each position was replaced by all other L-amino acids. The epitope-derived peptides were further characterized with respect to antibody affinity and their inhibition of the antibody-hIL-10 interaction. One antibody (CB/RS/11) binds to residues which are completely buried in the X-ray structure of IL-10. Accessibility of this hidden epitope is enhanced upon binding of the antibody CB/RS/2, which recognizes a discontinuous epitope located nearby. The recognition of the hidden CB/RS/11 epitope, as well as the cooperative binding behaviour of the two antibodies, provides evidence that IL-10 can adopt a conformational state other than that observed in the crystal structure.

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Crystal structure of interleukin-10 reveals the functional dimer with an unexpected topological similarity to interferon γ

Cited by 212 publications

References 50 publications

3D domain swapping: A mechanism for oligomer assembly

3D domain swapping: A mechanism for oligomer assembly

Structure and function of interleukin-22 and other members of the interleukin-10 family

Evidence for conformationally different states of interleukin-10: binding of a neutralizing antibody enhances accessibility of a hidden epitope

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