Perspective: Spectrin-Like Repeats in Dystrophin Have Unique Binding Preferences for Syntrophin Adaptors That Explain the Mystery of How nNOSμ Localizes to the Sarcolemma.

Justin M Percival

doi:10.3389/fphys.2018.01369

Abstract

Dystrophin is a massive multi-domain protein composed of specialized amino and carboxyl termini that are separated by 24 spectrin-like repeats. Dystrophin performs critical structural and signaling roles that are indispensable for the functional integrity of skeletal muscle. Indeed, the loss of dystrophin protein expression causes the muscle wasting disease, Duchenne muscular dystrophy (DMD). Substantial progress has been made in defining the functions of the domains of dystrophin, which has proven invaluable for the development of miniaturized dystrophin gene and exon skipping therapies for DMD. However, a long-standing mystery regarding dystrophin function is how dystrophin, and its adaptor and neuronal nitric oxide synthase mu (nNOSμ) binding partner α-syntrophin, cooperate to localize nNOSμ to the sarcolemma. Only when localized to the sarcolemma can nNOSμ override sympathetic vasoconstriction and prevent functional ischemia in contracting muscles. Current evidence suggests that spectrin-like repeat 17 of dystrophin and α-syntrophin cooperate to localize nNOSμ to the sarcolemma. However, the exact mechanism remains unclear and controversial because of equivocal evidence for direct binding of dystrophin and nNOSμ. Recently, an important study identified a novel α-syntrophin binding site within spectrin-like repeat 17, leading to a new model whereby α-syntrophin recruits nNOSμ to the sarcolemmal dystrophin complex by binding spectrin-like repeat 17. This model finally appears to solve the mystery of the dual requirement for dystrophin and α-syntrophin for sarcolemmal nNOSμ localization. The aim of the current perspective is to highlight this major advance in understanding of dystrophin’s role in localizing nNOSμ and its implications for current trials.

Highlights

Dystrophin is a massive multi-domain protein composed of specialized amino and carboxyl termini that are separated by 24 spectrin-like repeats
Studies in mdx mice and Becker muscular dystrophy patients that expressed a variety of truncated dystrophin proteins indicated that nNOSμ and α-syntrophin could associate with the sarcolemma independently of the two syntrophin binding sites (SBS) in dystrophin’s carboxyl terminus (Figure 1)
In dCTmdxdd mice α-syntrophin and nNOSμ could still be detected at the sarcolemma, α-syntrophin labeling was reduced as expected. These findings support the model that there are multiple α-syntrophin sites in dystrophin and α-dystrobrevin that are required for full sarcolemmal association of α-syntrophin, but that only the α-SBS within spectrin like repeat 17 is required for sarcolemma nNOSμ localization

Summary

Introduction

A recent study by Adams et al (2018), suggests a new model that may solve the mystery of the dual requirement for dystrophin and α-syntrophin for nNOSμ localization to the sarcolemma (Figure 1). Studies in mdx mice and Becker muscular dystrophy patients that expressed a variety of truncated dystrophin proteins indicated that nNOSμ and α-syntrophin could associate with the sarcolemma independently of the two syntrophin binding sites (SBS) in dystrophin’s carboxyl terminus (Figure 1).

Results

Conclusion