CDKL Family Kinases Have Evolved Distinct Structural Features and Ciliary Function

Peter Canning,Kwangjin Park,João Gonçalves,Chunmei Li,Conor J Howard,Timothy D Sharpe,Liam J Holt,Laurence Pelletier,Alex N Bullock,Michel R Leroux

doi:10.1016/j.celrep.2017.12.083

Abstract

SummaryVarious kinases, including a cyclin-dependent kinase (CDK) family member, regulate the growth and functions of primary cilia, which perform essential roles in signaling and development. Neurological disorders linked to CDK-Like (CDKL) proteins suggest that these underexplored kinases may have similar functions. Here, we present the crystal structures of human CDKL1, CDKL2, CDKL3, and CDKL5, revealing their evolutionary divergence from CDK and mitogen-activated protein kinases (MAPKs), including an unusual αJ helix important for CDKL2 and CDKL3 activity. C. elegans CDKL-1, most closely related to CDKL1–4 and localized to neuronal cilia transition zones, modulates cilium length; this depends on its kinase activity and αJ helix-containing C terminus. Human CDKL5, linked to Rett syndrome, also localizes to cilia, and it impairs ciliogenesis when overexpressed. CDKL5 patient mutations modeled in CDKL-1 cause localization and/or cilium length defects. Together, our studies establish a disease model system suggesting cilium length defects as a pathomechanism for neurological disorders, including epilepsy.

Highlights

Primary cilia are organelles found in most eukaryotic cells, including neurons, that perform essential roles in human sensory physiology, cell signaling, and development (May-Simera and Kelley, 2012; Mukhopadhyay and Rohatgi, 2014; Oh and Katsanis, 2012)
Unlike other transition zone (TZ) proteins, the sole C. elegans CDKL protein family member (CDKL-1), which localizes to the ciliary TZ (Li et al, 2016), does not regulate the diffusion barrier
We present evidence that human CDK-Like 5 (CDKL5) is a ciliary protein with a potential role in ciliogenesis, and we show that C. elegans CDKL-1 variants modeling CDKL5 human patient mutations exhibit cilium length defects, with or without loss of TZ localization

Summary

SUMMARY

Various kinases, including a cyclin-dependent kinase (CDK) family member, regulate the growth and functions of primary cilia, which perform essential roles in signaling and development. Neurological disorders linked to CDK-Like (CDKL) proteins suggest that these underexplored kinases may have similar functions. We present the crystal structures of human CDKL1, CDKL2, CDKL3, and CDKL5, revealing their evolutionary divergence from CDK and mitogen-activated protein kinases (MAPKs), including an unusual aJ helix important for CDKL2 and CDKL3 activity. C. elegans CDKL-1, most closely related to CDKL1–4 and localized to neuronal cilia transition zones, modulates cilium length; this depends on its kinase activity and aJ helix-containing C terminus. Human CDKL5, linked to Rett syndrome, localizes to cilia, and it impairs ciliogenesis when overexpressed. CDKL5 patient mutations modeled in CDKL-1 cause localization and/or cilium length defects. Our studies establish a disease model system suggesting cilium length defects as a pathomechanism for neurological disorders, including epilepsy

INTRODUCTION

C N-terminal lobe β1 β2

RESULTS AND DISCUSSION

EXPERIMENTAL PROCEDURES