Filamine

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Filamines (FLN) are proteins in eukaryotes and belong to the actin-binding proteins (ABP) . They are involved in the cross-linking of actin filaments , a main component of the cytoskeleton , as well as the cross-linking of actin filaments with proteins in the cell membrane . Indirectly, they also play an important role in cell-cell and cell-matrix connections , the movement of cells ( cell motility ) and the development of eukaryotes ( ontogenesis ). Mutations in the genes coding for filamin-B or -C can cause rare hereditary diseases.

nomenclature

For a long time the nomenclature was relatively inconsistent. Many different names or abbreviations can easily lead to confusion. A uniform nomenclature was only introduced in 2001. The abbreviation FLN can be preceded by a prefix that indicates from which organism the corresponding filamine was isolated, if this is not evident from the context:

The following table provides an overview of the various filamines:

Surname Old names Number of Units
hsFLNa ABP, ABP280, FLN1 Non-muscle FLN, αFLN, Filamin A. 24
hsFLNb βFLN, FH1, FLN3, Filamin B 24
hsFLNc γFLN, ABP-L, FLN2, Filamin C 24
ggFLNb FLN 24
ddFLN ABP120, gelation factor 6th
dmFLN1-20 Filamin-240, Filamin1 20th
dmFLN1-9 Filamin90 9
dmFLN2 20th

The filamines of man

construction

There are 3 different filamines in humans: Filamin A (α-Filamin), Filamin B (β-Filamin) and Filamin C (γ-Filamin). They consist of 24 repetitions, each made up of about 96 amino acids . At the carboxy-terminal (C-terminal) end, the filamines have a flexible joint region that is V- or Y-shaped in electron microscope images. They give the cross-links a certain flexibility. There are still 2 isoforms of filamines A and B, one with or without a second joint region.

Functions

The functions of filamines are numerous and are mediated by connections, mainly between actin and membrane proteins . More than 20 of these interactions are now known. The membrane proteins are often receptors that transmit signals into the cell when their ligands are bound (so-called signal transmission ). The connections of the filamines are released or newly formed via signals and can lead to a reorganization of the cytoskeleton. Signal transmission is mediated , among other things, by phosphorylation and dephosphorylation.

One example is the interaction of filamines A and B between actin and a receptor that occurs in blood platelets (thrombocytes) , the so-called Von Willebrand factor receptor. It plays an important role in the initiation of blood clotting. If the receptor binds its ligand , the Von Willebrand factor, then this connection activates the blood platelets and reorganizes the cytoskeleton. Another receptor that plays a role in blood clotting and that interacts with filamin is the tissue factor receptor .

Furthermore, cell-cell and cell-matrix connections can be dissolved or formed through the interaction with numerous integrins . For example, integrins bind to connective tissue structures outside the cell, such as collagen and filamin. They thus contribute to the stability of cell associations.

Filamin C has a specific amino acid sequence that interacts with the Z-disk of actin filaments in muscle cells. This leads to a cross-linking of the muscle fibrils and thus contributes to stabilization.

Filamin-associated diseases in humans

Mutations in the genes that code for the filamines can lead to numerous, but rare diseases.

Filamin A

For filamin A (FLNA), mutations and diseases resulting therefrom have been described which can lead to reduced or completely lost function ( loss of function ) as well as those which can cause overactivity and increased function ( gain of function ).

In the congenital syndromes with increased FLNA effect, skeletal dysplasias and deafness occur , including the otopalatodigital syndromes OPD type 1 and OPD type 2 and the Melnick-Needles syndrome .

Mutations that lead to a reduced effect of FLNA are summarized as FLNA-related disease (FLNA-associated disease). This is an X-linked dominant disease with a highly variable expression that is usually fatal in boys. Due to the clinical similarities, the FLNA-associated disease belongs to the group of connective tissue syndromes with Marfan syndrome , Ehlers-Danlos syndrome and Loeys-Dietz syndrome .

Common clinical manifestations include:

Filamin C

Mutations in the filamin C gene (FLNC) , for example, are the cause of filaminopathy , a form of myofibrillary myopathy (MFM). MFM are a clinically and genetically heterogeneous group of muscle diseases that are characterized by the focal dissolution of muscle fibrils and the abnormal accumulation and aggregation of various proteins in the muscle fibers of the patient. All of the FLNC mutations described so far concern the dimerization domain. For the p.W2710X mutation, which leads to a deletion of the carboxy-terminal 16 amino acids in domain 24, it could be shown that this disrupts the dimerization and the mutated filamine molecules instead assemble and form aggregates. In addition, the mutated filamin C is more unstable and more susceptible to proteolysis . Clinically, filaminopathy leads to slowly progressing muscle weakness that primarily affects the muscles near the trunk. Respiratory failure due to involvement of the respiratory muscles is a common and serious complication .

literature

Individual evidence

  1. ↑ a b T. P. Stossel et al.: Filamins as integrators of cell mechanics and signaling . In: Nat Rev Mol Cell Biol . 2 (2), 2001 Feb, pp. 138-145. PMID 11252955 .
  2. ↑ M. Knuth: Identification and characterization of FIP, a new filamin-binding protein. Dissertation. 2001. PDF version
  3. ↑ U. Tigges: Characterization of the interaction between the structural protein filamin and the protein kinase C α . Dissertation . 2003. PDF version
  4. ↑ Ted M. Kremer, Mark E. Lindsay, T. Bernard Kinane, Megan H. Hawley, Brent P. Little, Mari Mino-Kenudson: Case 28-2019: A 22-Year-Old Woman with Dyspnea and Chest Pain New England Journal of Medicine 2019, Volume 381, Issue 11 of September 12, 2019, pages 1059-1067, DOI: 10.1056 / NEJMcpc1904041