In myofibrils, there
are many proteins which combine and work together en masse to contract muscles,
e.g. actin, myosin, and tropomyosin. One such protein is nebulin, which
constitutes a family of proteins of a common characteristic (a series of
repeating 35 amino acids) with a variety of functions.
Nebulin, nearly four
times the size of the next contender in its family, is the most commonly known.
It has been labeled for decades as a molecular ruler which determines the
length of the associated actin filaments. However, recent studies suggest that
nebulin does not specify a certain length that the actin must adhere to;
rather, the nebulin acts as a regulator and stabilizer of the actin filament’s
length. Its loss has contributed to larger Z-disc widths and decreased force
production from the affected muscles.
N-RAP, or
Nebulin-Related Anchoring Protein, is the next-longest but not as interesting.
It is found in striated muscle and plays its major role in assembly of
myofibrils and actin filaments in the sarcomeres.
Nebulette is about a
sixth of nebulin’s length but is found only in cardiac muscle. At first,
nebulette was thought to be the “functional counterpart of nebulin in heart
muscle.” Despite its comparatively small size and localization to the Z-disc, nebulette
does function to stabilize the actin filament like its brother. Its superiority
to nebulin in cardiac muscle has been attributed by the paper to tropomyosin’s
dependence on nebulette for stability of the thin filament. In fact, mutations
of nebulette’s gene have correlated with DCM (dilated cardiomyopathy) in both
mice and humans, those in mice leading to severe heart failure.
The two final family
members, LASP-1 and LASP-2 are similar in domain structure, but have different
effects on the cell. Unlike LASP-1, LASP-2 may localize to different parts of
the cell, including the Z-discs and adhesion between cells. “It has been
speculated that LASP-2 acts as a molecular scaffold that is important for actin
filament and focal adhesion stabilization and organization.” LASP-1 has had
different roles throughout different studies, its loss contributing both to
decreased rates of cell migration and proliferation as well as increased rates
of cell migration and concentration. The discrepancy is explained by the
authors as “reconciled by the fact that the LASP-1 depletion studies represent
transient, incomplete reduction of LASP-1, whereas the LASP-1 knockout mouse is
a chronic, complete loss of LASP-1.” A lack of LASP-1 has been suggested to increase
the cell migration and number of tumors in breast, ovarian, and liver cancers,
contributing to its role in cell signaling, whatever it may precisely be.
Nebulin and its
family members are important constituents of muscles and contribute heavily to
our homeostasis. They are an interesting topic chiefly for their impact on the
material that will be on the next test, but also because of the specifics of
their functions that are not so widely known.
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