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.
| Original language | English (US) |
|---|---|
| Article number | 1369 |
| Journal | Frontiers in Physiology |
| Volume | 9 |
| Issue number | OCT |
| DOIs | |
| State | Published - Oct 8 2018 |
Fingerprint
Keywords
- Duchenne muscular dystrophy
- Dystrophin
- NNOS
- Spectrin-like repeat
- Syntrophin
ASJC Scopus subject areas
- Physiology
- Physiology (medical)
Cite this
Perspective : Spectrin-like repeats in dystrophin have unique binding preferences for syntrophin adaptors that explain the mystery of how nNOSμ localizes to the sarcolemma. / Percival, Justin M.
In: Frontiers in Physiology, Vol. 9, No. OCT, 1369, 08.10.2018.Research output: Contribution to journal › Review article
}
TY - JOUR
T1 - Perspective
T2 - Spectrin-like repeats in dystrophin have unique binding preferences for syntrophin adaptors that explain the mystery of how nNOSμ localizes to the sarcolemma
AU - Percival, Justin M.
PY - 2018/10/8
Y1 - 2018/10/8
N2 - 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.
AB - 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.
KW - Duchenne muscular dystrophy
KW - Dystrophin
KW - NNOS
KW - Spectrin-like repeat
KW - Syntrophin
UR - http://www.scopus.com/inward/record.url?scp=85055088170&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85055088170&partnerID=8YFLogxK
U2 - 10.3389/fphys.2018.01369
DO - 10.3389/fphys.2018.01369
M3 - Review article
AN - SCOPUS:85055088170
VL - 9
JO - Frontiers in Physiology
JF - Frontiers in Physiology
SN - 1664-042X
IS - OCT
M1 - 1369
ER -