Leiomodin

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Leiomodin
Mass / length primary structure 547 (LMOD 2) to 572 (LMOD 1) amino acids
Identifier
Gene name (s) LMOD
External IDs

Leiomodin is a protein with a weight of 64 to 80 kilodaltons that serves as a nucleation factor in the formation of actin filaments .

Shapes and structure

There are three different forms of leiomodin that are on three different genes:

  • Leiomodin-1 (LMOD 1) , also known as leiomodin muscle form , is 572 amino acids long and has a mass of 64 kilodaltons. Leiomdin-1 has a long, C-terminal polyproline sequence, probably a membrane-spanning region, and two types of tandem repeating sections. It occurs in all tissues tested so far (thyroid, eye muscles, skeletal muscles, ovaries, cerebellum, kidneys, pancreas, spleen, thymus and retina).
  • Leiomodin-2 (LMOD 2) , also known as cardiac leiomodin , is 547 amino acids long. Leiomodin-2 also has a long, C -terminal polyproline sequence. It occurs exclusively in the fetal and adult hearts and muscles of adults.
  • Leiomodin-3 (LMOD 3) , also known as fetal leiomodin , occurs specifically at the ends of sarcomeres of all striated muscles and has a mass of 80 kilodaltons. It has a tropomyosin- forming helix near the N -terminus , followed by an actin-binding helix, a glutamine- rich region, a leucine-rich repeat , a proline- rich region, a base region and a WAS protein homology-2 (WH2 ) domain .

function

Leimodin acts - especially in muscle cells - as a strong nucleation factor in the nucleation of actin (in other cell types, the Arp 2/3 complex and formin in particular have been identified as nucleation factors). Of the various sections of the protein, the smallest with a strong nucleation effect contains the leucine-rich repeat and the C -terminal extension. The N -termianle area increases the nucleation threefold and renews tropomyosin, which also weakly increases the nucleation and ensures the localization of the leiomodin in the middle of the sarcomere. Overall, leiomodin has three sites that can bind actin, which can lead to these three G-actin pieces joining together to form a nucleation core. Furthermore, in its first 340 amino acids, leiomodin corresponds to about 40% tropomodulin, a protein that covers the slow ( pointed end ) of the actin filament depending on tropomyosin. The N -terminal region of tropomodulin is unstructured, with the exception of three helical segments, which serve to bind tropomyosin twice and actin once. However, due to its C -terminal sequence, tropomodulin has another, tropomyosin-independent actin binding site which almost exactly matches the structure of a leucine-rich repeat . Leiomodin has exactly this structure, except for the fact that it only has a single tropomyosin binding site and that it is about 150 amino acids longer after the C terminus. These other amino acids contain, among other things, another binding site for actin.

Leiomodin-1

Leiomodin-1 was first discovered when scientists in the blood of patients suffering from Hashimoto's thyroiditis , were sick for a antigen were that both the thyroid , and in the muscles of the eyes expressed will. This search took place because a small proportion of Hashimoto's thyroiditis sufferers also have an autoimmune disease of the eyes, such as endocrine orbitopathy . In fact, they found a complementary DNA that codes for LMOD 1. Further blood tests have shown that leiomidin-1 is expressed in the thyroid gland and eye muscles, and that antigens to leiomidin-1 are found in the blood of 8 out of 34 patients with autoimmune thyroid disease, but none of them.

Leiomodin-2

Leiomodin-2 was found when the EST database was searched for sequences similar to that of tropomodulin . The gene for leiomodin-2 is located on chromosome bands 7q31 - q32 . In addition to its ability to increase actin polymerization , leiomodin-2 also binds N -terminal α-tropomyosin .

Leiomodin-3

M. Yuen and others managed to replicate leiomodin-3 in 2014. This was part of a study looking for genetic causes for nemaline myopathy . In fact, the researchers found that 21 patients out of 14 families with nemaline myopathy had changes in the LMOD 3 gene. Changes in LMOD-3 result in shortened and disorganized actin filaments; switching off LMOD-3 in zebrafish resulted in pathological manifestations similar to those of nemaline myopathy.

Leiomodin-3 also forms N -terminal tropomyosin, but the binding affinity of leiomodin-2 is stronger.

Individual evidence

  1. ↑ a b c Leiomodin.  In: Online Mendelian Inheritance in Man . (English)
  2. ↑ a b c d e Leiomodin.  In: Online Mendelian Inheritance in Man . (English)
  3. Jump up ↑ D. Chereau, M. Boczkowska, A. Skwarek-Maruszewska, I. Fujiwara, DB Hayes, G. Rebowski, P. Lappalainen, TD Pollard and R. Dominguez: Leiomodin is an actin filament nucleator in muscle cells . In: Science . 320, No. 5873, April 2008, pp. 239-243. doi : 10.1126 / science.1155313 . PMID 18403713 . PMC 2845909 (free full text).
  4. ↑ UniProtKB - P29536 (LMOD1_HUMAN)
  5. ^ A b C. A. Conley, KL Fritz-Six, A. Almenar-Queralt and VM Fowler: Leiomodins: larger members of the tropomodulin (Tmod) gene family . In: Genomics . 73, No. 2, April 2001, pp. 127-139. PMID 11318603 .
  6. ↑ ZG Zhang, JR Wall and NF Bernard: Tissue distribution and quantitation of a gene expressing a 64-kDa antigen associated with thyroid-associated ophthalmopathy . In: Clinical Immunology and Immunopathology . 80, No. 3, September 1996, pp. 236-244. PMID 8811043 .
  7. ↑ UniProtKB - Q6P5Q4 (LMOD2_HUMAN)
  8. ↑ a b Leiomodin.  In: Online Mendelian Inheritance in Man . (English)
  9. ↑ UniProtKB - Q0VAK6 (LMOD3_HUMAN)
  10. ↑ David Chereau, Malgorzata Boczkowska, Aneta Skwarek-Maruszewska, Ikuko Fujiwara, David B. Hayes, Grzegorz Rebowski, Pekka Lappalainen, Thomas D. Pollard and Roberto Dominguez: Leiomodin is an Actin Filament Nucleator in Muscle Cells . In: Science . 320, No. 5873, April 2008, pp. 239-243. doi : 10.1126 / science.1155313 . PMC 2845909 (free full text).
  11. ^ Q. Dong, M. Ludgate and G. Vassart: Cloning and sequencing of a novel 64-kDa autoantigen recognized by patients with autoimmune thyroid disease . In: The Journal of Endocrinology and Metabolism . 72, No. 6, June 1999, pp. 1375-1381. doi : 10.1210 / jcem-72-6-1375 . PMID 2026759 .
  12. ↑ M. Yuen et al .: Leiomodin-3 dysfunction results in thin filament disorganization and nemaline myopathy . In: The Journal of Clinical Investigation . 124, No. 11, November 2014, pp. 4693-4708. doi : 10.1172 / JCI75199 . PMID 25250574 . PMC 4347224 (free full text).