Abstract
Ankyrins together with their spectrin partners are the master organizers of micron-scale membrane domains in diverse tissues. The 24 ankyrin (ANK) repeats of ankyrins bind to numerous membrane proteins, linking them to spectrin-based cytoskeletons at specific membrane microdomains. The accessibility of the target binding groove of ANK repeats must be regulated to achieve spatially defined functions of ankyrins/target complexes in different tissues, though little is known in this regard. Here we systemically investigated the autoinhibition mechanism of ankyrin-B/G by combined biochemical, biophysical and structural biology approaches. We discovered that the entire ANK repeats are inhibited by combinatorial and quasi-independent bindings of multiple disordered segments located in the ankyrin-B/G linkers and tails, suggesting a mechanistic basis for differential regulations of membrane target bindings by ankyrins. In addition to elucidating the autoinhibition mechanisms of ankyrins, our study may also shed light on regulations on target bindings by other long repeat-containing proteins.
Highlights
Ankyrins are a widely expressed scaffold protein family, which mainly function to link great varieties of functionally related but structurally diverse integral membrane proteins to the spectrin-based cytoskeletons (Bennett and Baines, 2001; Bennett and Healy, 2009; Bennett and Lorenzo, 2013)
Ankyrins are master scaffold proteins assembling very diverse signaling microdomains beneath membrane bilayers. This is achieved by their membrane binding domain (MBD)-mediated bindings to numerous trans-membrane proteins and spectrin binding (SBD)-mediated anchoring of the protein complex to spectrin-based cytoskeletal meshwork
Formation of a highly elongated and malleable target binding groove by the 24 ANK repeats with multiple semi-independent target binding sites provides a mechanistic explanation to how ankyrin MBD, via combinatorial usages of its target binding sites, can bind to many distinct membrane targets with high specificity (Figure 7A; and Wang et al, 2014)
Summary
Ankyrins are a widely expressed scaffold protein family, which mainly function to link great varieties of functionally related but structurally diverse integral membrane proteins to the spectrin-based cytoskeletons (Bennett and Baines, 2001; Bennett and Healy, 2009; Bennett and Lorenzo, 2013). The ankyrin family consists of three members: ankyrin-R (AnkR), ankyrin-B (AnkB) and ankyrin-G (AnkG). They share similar domain organizations (Figure 1A), but usually locate at different subcellular regions and perform divergent physiological functions (Mohler et al, 2002; Abdi et al, 2006; He et al, 2013; Bennett and Lorenzo, 2016). Each ankyrin contains an N-terminal membrane binding domain (MBD), which is composed of 24 ANK repeats and responsible for binding to diverse membrane targets.
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