Abstract
Ankyrin adaptors together with their spectrin partners coordinate diverse ion channels and cell adhesion molecules within plasma membrane domains and thereby promote physiological activities including fast signaling in the heart and nervous system. Ankyrins specifically bind to numerous membrane targets through their 24 ankyrin repeats (ANK repeats), although the mechanism for the facile and independent evolution of these interactions has not been resolved. Here we report the structures of ANK repeats in complex with an inhibitory segment from the C-terminal regulatory domain and with a sodium channel Nav1.2 peptide, respectively, showing that the extended, extremely conserved inner groove spanning the entire ANK repeat solenoid contains multiple target binding sites capable of accommodating target proteins with very diverse sequences via combinatorial usage of these sites. These structures establish a framework for understanding the evolution of ankyrins' membrane targets, with implications for other proteins containing extended ANK repeat domains.
Highlights
Ankyrins are a family of scaffold proteins which play essential roles in connecting numerous ion channels, cell adhesion molecules, and receptors to the spectrin-based cytoskeleton beneath membranes and thereby provide mechanical support for plasma membranes and control the activities of excitable tissues including neurons and muscles (Bennett and Chen, 2001; Bennett and Healy, 2009)
There are three members in the human ankyrin family: ankyrin-R/B/G (AnkR/B/G) encoded by ANK1/2/3, respectively. They all consist of a highly similar N-terminal membrane binding domain composed of 24 ankyrin (ANK) repeats, a spectrin-binding domain comprised of two ZU5 domains, and a UPA domain followed by a death domain (DD) and a variable C-terminal regulatory domain (Bennett and Lorenzo, 2013) (Figure 1A)
The C-terminal regulatory domains have been reported to bind to ANK repeats intra-molecularly and modulate the target binding properties of ankyrins (Davis et al, 1992; Abdi et al, 2006)
Summary
Ankyrins are a family of scaffold proteins which play essential roles in connecting numerous ion channels, cell adhesion molecules, and receptors to the spectrin-based cytoskeleton beneath membranes and thereby provide mechanical support for plasma membranes and control the activities of excitable tissues including neurons and muscles (Bennett and Chen, 2001; Bennett and Healy, 2009). There are three members in the human ankyrin family: ankyrin-R/B/G (AnkR/B/G) encoded by ANK1/2/3, respectively They all consist of a highly similar N-terminal membrane binding domain composed of 24 ankyrin (ANK) repeats, a spectrin-binding domain comprised of two ZU5 domains, and a UPA domain followed by a death domain (DD) and a variable C-terminal regulatory domain (Bennett and Lorenzo, 2013) (Figure 1A). Loss-of-function mutations can cause hemolytic anemia (Gallagher, 2005), various cardiac diseases including several cardiac arrhythmia syndromes and sinus node dysfunction (Mohler et al, 2003, 2007; Le Scouarnec et al, 2008; Hashemi et al, 2009), bipolar disorder (Ferreira et al, 2008; Dedman et al, 2012; Rueckert et al, 2013), and autism spectrum disorder (Iqbal et al, 2013; Shi et al, 2013)
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