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The Dystrophin Complex: Structure, Function, and Implications for Therapy

Quan Q. Gao, Elizabeth M. McNally

10.1002/cphy.c140048

Source: Volume 5, Issue 3, July 2015

Published online: June 2015

Full Article on Wiley Online Library



ABSTRACT

The dystrophin complex stabilizes the plasma membrane of striated muscle cells. Loss of function mutations in the genes encoding dystrophin, or the associated proteins, trigger instability of the plasma membrane, and myofiber loss. Mutations in dystrophin have been extensively cataloged, providing remarkable structure‐function correlation between predicted protein structure and clinical outcomes. These data have highlighted dystrophin regions necessary for in vivo function and fueled the design of viral vectors and now, exon skipping approaches for use in dystrophin restoration therapies. However, dystrophin restoration is likely more complex, owing to the role of the dystrophin complex as a broad cytoskeletal integrator. This review will focus on dystrophin restoration, with emphasis on the regions of dystrophin essential for interacting with its associated proteins and discuss the structural implications of these approaches. © 2015 American Physiological Society. Compr Physiol 5:1223‐1239, 2015.

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Figure 1. Figure 1. Dystrophin‐glycoprotein complex (DGC). Dystrophin is a rod shape protein that links intracellular cytoskeleton network to transmembrane components of the DGC, including dystroglycan, sarcoglycans, and sarcospan. Dystroglycan is composed of two subunits, α and β. α‐Dystroglycan is an extracellular peripheral membrane protein and a receptor for laminin‐2, linking the DGC to the ECM. The sarcoglycans form a tight complex with sarcospan, strengthening the connection between α and β‐dystroglycans. Besides a structural role, the sarcoglycan‐sarcospan subcomplex is also involved in signal transduction and mechanoprotection. α‐Dystroglycan is heavily O‐glycosylated (straight lines) in the central mucin domain. β‐Dystroglycan and the sarcoglycans contain potential N‐glycosylation sites (branch). The syntrophins, dystrobrevins, and nNOS are recruited to the C‐terminus of dystrophin and participate in signal transduction pathways.
Figure 2. Figure 2. Dystrophin functional domains and mini‐/micro‐dystrophin constructs. (A) Dystrophin protein has four major functional domains. The N‐terminal actin‐binding domain (ABD1, shown in blue) contains two calponin‐homology (CH) motifs. The central rod domain is composed of 24 spectrin‐like repeats (R1‐R24, shown in white) interrupted by the proline‐rich hinges (H1‐H4, shown in yellow). A second actin‐binding domain (ABD2) spans R11‐R17. The cysteine‐rich domain (CR, shown in yellow) and part of H4 form the binding site for β‐dystroglycan (DgBD). The C‐terminus (CT, shown in gray) contains binding sites for syntrophins (SBD) and dystrobrevin (DbBD). (B) Domain structure of the internally truncated dystrophin constructs discussed in the text. Note that exons 17 to 48 deletions (Δ17‐48) retain a partial R19. The molecular weights are shown to the right of the constructs.
Figure 3. Figure 3. Phasing of spectrin repeats with dystrophin has functional consequences. (A) The central rod of dystrophin is composed of 24 spectrin‐like repeats. Each repeat unit is ∼110 aa in size and forms a triple α‐helical bundle; a and b form the long helix while c forms the short helix. (B) In the normal dystrophin protein, repeat 19 and repeat 20 is separated by hinge 3. (C) The exon Δ17‐48 deletion retains the last half of b helix and full c helix from R19 in the protein, producing an extra helical region that may disrupt the folding pattern of the protein. (D) The ΔH2‐R19 construct removes the partial R19 that is retained in the Δ17‐48 deletions, resulting in an overall structure identical to that of the normal protein. Maintaining the triple helical structure of each repeat is important for its molecular function. When expressed in the mdx mice, ΔH2‐R19 construct has a better rescue effects than the Δ17‐48 construct (79). Furthermore, clinical observations show that BMD patients carrying deletions that disrupt repeat phasing develop cardiomyopathy 10 years earlier than those carrying deletions that retain the correct phasing of the repeat (91).
Figure 4. Figure 4. The sarcoglycan complex. Six sarcoglycans have been identified in mammals. α‐ and ϵ‐sarcoglycans are type I transmembrane proteins and are ∼60% related. α‐ and ϵ‐sarcoglycan genes likely arose from a single gene duplication event since they also have an identical intron‐exon structure. There is a single gene related to both α‐ and ϵ‐sarcoglycan in invertebrates. γ‐, δ‐, and ζ‐ are type II transmembrane proteins. These three sarcoglycans have identical gene structure and are ∼70% similar in protein sequence. There is a single gene related to γ‐, δ‐, and ζ‐sarcoglycan in invertebrates, suggesting that they arose from multiple gene duplication events. β‐Sarcoglycan is also a type II transmembrane protein but is only weakly related to these sarcoglycans. Conserved cysteine residues at the C‐terminus of β, δ, γ, and ζ are necessary for intramolecular disulfide bond formation (39). In striated muscle, the major sarcoglycan complex is composed of α‐, β‐, γ‐, and δ‐sarcoglycan (left). In vascular smooth muscle, the major sarcoglycan complex contains ϵ‐, β‐, ζ‐, and δ‐sarcoglycan (middle). In invertebrates (Drosophila and C elegans), there are only three sarcoglycans, α/ϵ‐, γ/δ/ζ‐, and β‐sarcoglycan (right).
Figure 5. Figure 5. Sarcoglycan complex assembly and sarcolemmal targeting. (A) The assembly of the sarcoglycan complex follows a specific path after protein translation. First, β‐sarcoglycan interacts with δ‐sarcoglycan to form the complex core. γ‐sarcoglycan then associates with the β‐δ core. Finally, α‐sarcoglycan completes the formation of the complex. Deficiency in any sarcoglycan gene impairs the complex formation and plasma membrane translocation. (B) The sarcoglycan complex formation occurs in the ER. From Golgi to the sarcolemma, the sarcoglycans become associates with dystroglycan and sarcospan. At the sarcolemma, dystrophin reinforces the membrane localization of the sarcoglycans. In the absence of dystrophin, the sarcoglycan complex is also lost from the sarcolemma.


Figure 1. Dystrophin‐glycoprotein complex (DGC). Dystrophin is a rod shape protein that links intracellular cytoskeleton network to transmembrane components of the DGC, including dystroglycan, sarcoglycans, and sarcospan. Dystroglycan is composed of two subunits, α and β. α‐Dystroglycan is an extracellular peripheral membrane protein and a receptor for laminin‐2, linking the DGC to the ECM. The sarcoglycans form a tight complex with sarcospan, strengthening the connection between α and β‐dystroglycans. Besides a structural role, the sarcoglycan‐sarcospan subcomplex is also involved in signal transduction and mechanoprotection. α‐Dystroglycan is heavily O‐glycosylated (straight lines) in the central mucin domain. β‐Dystroglycan and the sarcoglycans contain potential N‐glycosylation sites (branch). The syntrophins, dystrobrevins, and nNOS are recruited to the C‐terminus of dystrophin and participate in signal transduction pathways.


Figure 2. Dystrophin functional domains and mini‐/micro‐dystrophin constructs. (A) Dystrophin protein has four major functional domains. The N‐terminal actin‐binding domain (ABD1, shown in blue) contains two calponin‐homology (CH) motifs. The central rod domain is composed of 24 spectrin‐like repeats (R1‐R24, shown in white) interrupted by the proline‐rich hinges (H1‐H4, shown in yellow). A second actin‐binding domain (ABD2) spans R11‐R17. The cysteine‐rich domain (CR, shown in yellow) and part of H4 form the binding site for β‐dystroglycan (DgBD). The C‐terminus (CT, shown in gray) contains binding sites for syntrophins (SBD) and dystrobrevin (DbBD). (B) Domain structure of the internally truncated dystrophin constructs discussed in the text. Note that exons 17 to 48 deletions (Δ17‐48) retain a partial R19. The molecular weights are shown to the right of the constructs.


Figure 3. Phasing of spectrin repeats with dystrophin has functional consequences. (A) The central rod of dystrophin is composed of 24 spectrin‐like repeats. Each repeat unit is ∼110 aa in size and forms a triple α‐helical bundle; a and b form the long helix while c forms the short helix. (B) In the normal dystrophin protein, repeat 19 and repeat 20 is separated by hinge 3. (C) The exon Δ17‐48 deletion retains the last half of b helix and full c helix from R19 in the protein, producing an extra helical region that may disrupt the folding pattern of the protein. (D) The ΔH2‐R19 construct removes the partial R19 that is retained in the Δ17‐48 deletions, resulting in an overall structure identical to that of the normal protein. Maintaining the triple helical structure of each repeat is important for its molecular function. When expressed in the mdx mice, ΔH2‐R19 construct has a better rescue effects than the Δ17‐48 construct (79). Furthermore, clinical observations show that BMD patients carrying deletions that disrupt repeat phasing develop cardiomyopathy 10 years earlier than those carrying deletions that retain the correct phasing of the repeat (91).


Figure 4. The sarcoglycan complex. Six sarcoglycans have been identified in mammals. α‐ and ϵ‐sarcoglycans are type I transmembrane proteins and are ∼60% related. α‐ and ϵ‐sarcoglycan genes likely arose from a single gene duplication event since they also have an identical intron‐exon structure. There is a single gene related to both α‐ and ϵ‐sarcoglycan in invertebrates. γ‐, δ‐, and ζ‐ are type II transmembrane proteins. These three sarcoglycans have identical gene structure and are ∼70% similar in protein sequence. There is a single gene related to γ‐, δ‐, and ζ‐sarcoglycan in invertebrates, suggesting that they arose from multiple gene duplication events. β‐Sarcoglycan is also a type II transmembrane protein but is only weakly related to these sarcoglycans. Conserved cysteine residues at the C‐terminus of β, δ, γ, and ζ are necessary for intramolecular disulfide bond formation (39). In striated muscle, the major sarcoglycan complex is composed of α‐, β‐, γ‐, and δ‐sarcoglycan (left). In vascular smooth muscle, the major sarcoglycan complex contains ϵ‐, β‐, ζ‐, and δ‐sarcoglycan (middle). In invertebrates (Drosophila and C elegans), there are only three sarcoglycans, α/ϵ‐, γ/δ/ζ‐, and β‐sarcoglycan (right).


Figure 5. Sarcoglycan complex assembly and sarcolemmal targeting. (A) The assembly of the sarcoglycan complex follows a specific path after protein translation. First, β‐sarcoglycan interacts with δ‐sarcoglycan to form the complex core. γ‐sarcoglycan then associates with the β‐δ core. Finally, α‐sarcoglycan completes the formation of the complex. Deficiency in any sarcoglycan gene impairs the complex formation and plasma membrane translocation. (B) The sarcoglycan complex formation occurs in the ER. From Golgi to the sarcolemma, the sarcoglycans become associates with dystroglycan and sarcospan. At the sarcolemma, dystrophin reinforces the membrane localization of the sarcoglycans. In the absence of dystrophin, the sarcoglycan complex is also lost from the sarcolemma.
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Article Title: The Dystrophin Complex: Structure, Function, and Implications for Therapy
 

How to Cite

Quan Q. Gao, Elizabeth M. McNally. The Dystrophin Complex: Structure, Function, and Implications for Therapy. Compr Physiol 2015, 5: 1223-1239. doi: 10.1002/cphy.c140048