8iw0
Crystal structure of the KANK1/liprin-beta1 complex
Structural highlights
DiseaseKANK1_HUMAN Inherited congenital spastic tetraplegia. The disease is caused by mutations affecting the gene represented in this entry. FunctionLIPB1_MOUSE May regulate the disassembly of focal adhesions. Did not bind receptor-like tyrosine phosphatases type 2A (By similarity).KANK1_HUMAN Involved in the control of cytoskeleton formation by regulating actin polymerization. Inhibits actin fiber formation and cell migration. Inhibits RhoA activity; the function involves phosphorylation through PI3K/Akt signaling and may depend on the competetive interaction with 14-3-3 adapter proteins to sequester them from active complexes. Inhibits the formation of lamellipodia but not of filopodia; the function may depend on the competetive interaction with BAIAP2 to block its association with activated RAC1. Inhibits fibronectin-mediated cell spreading; the function is partially mediated by BAIAP2. Inhibits neurite outgrowth. Involved in the establishment and persistence of cell polarity during directed cell movement in wound healing. In the nucleus, is involved in beta-catenin-dependent activation of transcription. Potential tumor suppressor for renal cell carcinoma.[1] [2] [3] [4] Publication Abstract from PubMedFocal adhesions (FAs) are dynamic protein assemblies that connect cytoskeletons to the extracellular matrix and are crucial for cell adhesion and migration. KANKs are scaffold proteins that encircle FAs and act as key regulators of FA dynamics, but the molecular mechanism underlying their specified localization and functions remains poorly understood. Here, we determine the KANK1 structures in complex with talin and liprin-beta, respectively. These structures, combined with our biochemical and cellular analyses, demonstrate how KANK1 scaffolds the FA core and associated proteins to modulate the FA shape in response to mechanical force. Additionally, we find that KANK1 undergoes liquid-liquid phase separation (LLPS), which is important for its localization at the FA edge and cytoskeleton connections to FAs. Our findings not only indicate the molecular basis of KANKs in bridging the core and periphery of FAs but also provide insights into the LLPS-mediated dynamic regulation of FA morphology. KANK1 shapes focal adhesions by orchestrating protein binding, mechanical force sensing, and phase separation.,Guo K, Zhang J, Huang P, Xu Y, Pan W, Li K, Chen L, Luo L, Yu W, Chen S, He S, Wei Z, Yu C Cell Rep. 2023 Oct 23;42(11):113321. doi: 10.1016/j.celrep.2023.113321. PMID:37874676[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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