Hidden Multivalency in Phosphatase Recruitment by a Disordered AKAP Scaffold: Hidden multivalency in a disordered scaffold

Matthew Watson, Teresa B. Almeida, Arundhati Ray, Christina Hanack, Rory Elston, Joan Btesh, Peter A. McNaughton, Katherine Stott*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


Disordered scaffold proteins provide multivalent landing pads that, via a series of embedded Short Linear Motifs (SLiMs), bring together the components of a complex to orchestrate precise spatial and temporal regulation of cellular processes. One such protein is AKAP5 (previously AKAP79), which contains SLiMs that anchor PKA and Calcineurin, and recruit substrate (the TRPV1 receptor). Calcineurin is anchored to AKAP5 by a well-characterised PxIxIT SLiM. Here we show, using a combination of biochemical and biophysical approaches, that the Calcineurin PxIxIT-binding groove also recognises several hitherto unknown lower-affinity SLiMs in addition to the PxIxIT motif. We demonstrate that the assembly is in reality a complex system with conserved SLiMs spanning a wide affinity range. The capture is analogous to that seen for many DNA-binding proteins that have a weak non-specific affinity for DNA outside the canonical binding site, but different in that it involves (i) two proteins, and (ii) hydrophobic rather than electrostatic interactions. It is also compatible with the requirement for both stable anchoring of the enzyme and responsive downstream signalling. We conclude that the AKAP5 C-terminus is enriched in lower-affinity/mini-SLiMs that, together with the canonical SLiM, maintain a structurally disordered but tightly regulated signalosome.

Original languageEnglish
Article number167682
JournalJournal of Molecular Biology
Issue number16
Publication statusPublished - 30 Aug 2022


  • A-kinase anchoring protein (AKAP)
  • Calcineurin
  • intrinsically disordered protein
  • multivalency
  • short linear motif (SLiM)


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