Creating functional sophistication from simple protein building blocks, exemplified by factor H and the regulators of complement activation

Elisavet Makou, Andrew P. Herbert, Paul N. Barlow*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Complement control protein modules (CCPs) occur in numerous functionally diverse extracellular proteins. Also known as short consensus repeats (SCRs) or sushi domains each CCP contains approximately 60 amino acid residues, including four consensus cysteines participating in two disulfide bonds. Varying in length and sequence, CCPs adopt a β-sandwich type fold and have an overall prolate spheroidal shape with N- and C-termini lying close to opposite poles of the long axis. CCP-containing proteins are important as cytokine receptors and in neurotransmission, cell adhesion, blood clotting, extracellular matrix formation, haemoglobin metabolism and development, but CCPs are particularly well represented in the vertebrate complement system. For example, factor H (FH), a key soluble regulator of the alternative pathway of complement activation, is made up entirely from a chain of 20 CCPs joined by short linkers. Collectively, therefore, the 20 CCPs of FH must mediate all its functional capabilities. This is achieved via collaboration and division of labour among these modules. Structural studies have illuminated the dynamic architectures that allow FH and other CCP-rich proteins to perform their biological functions. These are largely the products of a highly varied set of intramolecular interactions between CCPs. The CCP can act as building block, spacer, highly versatile recognition site or dimerization mediator. Tandem CCPs may form composite binding sites or contribute to flexible, rigid or conformationally 'switchable' segments of the parent proteins.

Original languageEnglish
Pages (from-to)812-818
Number of pages7
JournalBiochemical Society Transactions
Volume43
Issue number5
DOIs
Publication statusPublished - 1 Oct 2015

Keywords

  • CCPs
  • Protein architecture
  • Protein modules
  • SCRs
  • Sushi domains

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