19. Key functional proteins in skeletal muscle Flashcards
What is the structure of a muscle fibre?
Skeletal muscle fibres are composed of bundles of myofibrils which are segmented into functional units called “sarcomeres”.
What is a sarcomere?
basic unit of measure within muscle, defined as the portion between two adjacent Z lines
It is the functional unit of a myofibril.
- contains:
- Nebulin to help align actin
- Titin to provide elasticity and stabilises myosin
- M line in the middle
- Actin & myosin
What is a costamere?
Rib like structures (=”Costal”) on the surface of the sarcolemma
They are specialised sites of transmembrane complexes, occurring over the entire sarcolemma, where the transmission of force is concentrated
Found specifically at the Z disk
The 3 states of transmembrane linkage - force transmission through costameres
A. relaxed
B. Contracted, forces transmitted
C. Contracted, forces not transmitted - TM complexes not linked to ECM
Where is the Vinculin-Talin-Integrin complex usually localised?
usually localised in adherence junctions, involved in cell adhesion, cell migration, also sometimes cell proliferation
integrin acts as a receptor for laminin at the basal lamina, link to proteins at Z line with interaction with vinculin-talin
α7β1 integrin - what are integrins composed of? And which isoforms are the most common?
Integrins are heterodimers composed of an α and β subunit.
22 heterodimers have been identified, composed of 16 α chains and 8 β chains
The α7B and β1D isoforms are the most common integrins found in adult skeletal muscle.
What is the function of the α7β1 integrin?
- Mediate the processes of cell adhesion & migration
- Regulate the intracellular organisation of the actin cytoskeleton
- Important role in many signalling processes
Talin 1 vs talin 2.
Talin 2 is expressed at higher levels in skeletal muscle than talin 1
Both have a talin head and talin rod.
Describe the role of talin 1.
- interacts with the cytoplasmic domain of β1 integrin and with focal adhesion kinase (FAK) and vinculin
- also binds to F-actin to establish a link between β1 integrins and the cytoskeleton (more mechanical function)
What happens when the talin 1 (TIn1) gene is lost in SM?
Leads to progressive myopathy caused by mechanical failure of myotendinous junctions (MTJs).
What happens when the talin 2 gene is lost?
Mice lacking talin 2 are viable and fertile but develop a myopathy with centrally located nuclei that is associated with defects in the maintenance of MTJs.
What happens when you lose both talin 1 and 2?
SEVERE FUNCTIONAL OUTCOME
Severe defects in myoblast fusion and sarcomere assembly.
*talin 1 and 2 are somewhat mutually exclusive but can perform same function
Describe the structure of vinculin.
1066 aa
Has 4 Vh subdomains:
Vh 1 - talin, α-actinin, α-catenin, IpaA
Linker region: signalling intermediate
Arp 2/3, ponsin, vinexin, VASP
Vt region: how it interacts with actin
F-actin, PIP2, paxillin
What is vinculin involved in? And what is the result of mutations in its splice variant?
Vinculin is a membrane-cytoskeletal protein involved in linkage of integrin to the actin cytoskeleton.
Muscle specific splice variant = Metavinculin
*Mutations in metavinculin are assoc. with Idiopathic dilated cardiomyopathy (DCM) in humans
What does the Dystrophin-Glycoprotein Complex do & where is it found?
It is specific to striated muscle fibres and is aka dystrophin associated complex. DGC is localised at costameres.
It is a multimeric protein complex that acts to link the basal lamina to the actin cytoskeleton in SM fibres.