Group:MUZIC:Nebulin

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Contents 1 Introduction 2 Function and related diseases 3 Domains and interactions 3.1 Glutamic rich region 3.2 Nebulin modules 3.3 Serine rich region 3.4 SH3 domain 4 References

Introduction

spinqualitylabelsall models NMR structure of the SH3 domain of Nebulin Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image Nebulin (UniProt ID: P20929 [1]) is a very large filamentous protein (600-900 kDa) [1] tightly associated to the thin filament of the muscle sarcomere throughout its length. Nebulin is mostly found within the sarcomeres of skeletal muscles but was also identified at a low level in cardiac muscle cells [2]. However, the sarcomeres of cardiac muscles predominantly contain a Nebulin-like protein called Nebulette (UniProt ID: O76041 [2]) which is a "short version" of Nebulin (100 kDa), highly similar to its C-terminal part [3].

Function and related diseases

The Nebulin protein is involved in the structural integrity of the sarcomeres and is linked to many signalling pathways crucial for the maintenance of the sarcomere. The main fucntions of Nebulin are ^[4]:

• To define and regulate the length of the thin filaments of actin (molecular ruler);
• To maintain the alignment of adjacent myofibrills (linker of adjacent Z-disks);
• To regulate muscle contraction (regulator of cross-bridge cycles).

Mutations in the Nebulin encoding gene are the most common cause of Nemaline myopathy (NM), a non-dystrophic congenital muscle disorder characterised by muscle weakness.

Domains and interactions

Glutamic rich region

Nebulin modules

The Nebulin modules are 35 residues long modules for which no structural information is available.

• Tropomodulin: The N-terminal modules bind Tropomodulin at the pointed end of the thin filament of Actin.
• Actin: Each Nebulin module is able to bind to a monomer of F-Actin in a way that would control the length of the thin filament of Actin.
• Tropomyosin/Troponin: The central super-repeats of 7 Neb modules binds 1 Tropomyosin/Troponin complex.
• Myosin and Myosin Binding Protein C: The central super-repeats were also shown to bind Myosin in a way that would regulate the actomyosin activity.
• Calmodulin: The N-terminal and C-terminal super-repeats can bind Calmodulin in a Calcium-independant manner.
• Desmin: The C-terminal modules located close to the Z-disk bind Desmin, which is likely to play a role in the alignment of adjacent myofibrills.
• Alpha-Actinin: The C-terminal modules located within the Z-disk bind Alpha-Actinin

Serine rich region

The Ser-rich region has no homology to known structural motifs. The Serine residues can be phosphorylated by GSK3-ß in a way that modulates some of the Nebulin interactions.

SH3 domain

The Nebulin SH3 domain adopts a ß-Barrel . The SH3 domain is the only domain of Nebulin for which a 3D structure is available.

References

1. ↑ Wang K. Cytoskeletal matrix in striated muscle: the role of titin, nebulin and intermediate filaments. Adv Exp Med Biol. 1984;170:285-305. PMID:6547565
2. ↑ Kazmierski ST, Antin PB, Witt CC, Huebner N, McElhinny AS, Labeit S, Gregorio CC. The complete mouse nebulin gene sequence and the identification of cardiac nebulin. J Mol Biol. 2003 May 9;328(4):835-46. PMID:12729758
3. ↑ Moncman CL, Wang K. Nebulette: a 107 kD nebulin-like protein in cardiac muscle. Cell Motil Cytoskeleton. 1995;32(3):205-25. PMID:8581976 doi:http://dx.doi.org/10.1002/cm.970320305
4. ↑ Ottenheijm CA, Granzier H. Lifting the nebula: novel insights into skeletal muscle contractility. Physiology (Bethesda). 2010 Oct;25(5):304-10. PMID:20940435 doi:10.1152/physiol.00016.2010