1 / 17

Discovery of Relaxin

Discovery of Relaxin.

maille
Download Presentation

Discovery of Relaxin

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Discovery of Relaxin Relaxin was discovered by F. L. Hisaw [Proc. Soc. Exp. Biol. Med. 23,661 (1962)] and received its name from Fevold et al. [J. Am. Chem. Soc. 52, 3340 (1930)] who obtained a crude aqueous extract of this hormone from sow corpora lutea. A multitude of observations with crude relaxin preparations led to the view that relaxin probably plays an important role during pregnancy and parturition. The availability of purified relaxin has enabled the amino acid sequence determination of relaxin from pig [James et al., Nature 267, 544 (1977); Schwabe et al., Biophys. Res. Commun. 75, 503 (1977)], rat [John et al., Endocrinology 108, 726 (1981)] and shark [Schwabe et al., Ann. N.Y. Acad. Sci. 380, 6 (1982)].

  2. Overview of Relaxin Relaxin is naturally produced in all of us. A relatively low-molecular weight protein, relaxin is closely related to another important hormone in our body, insulin. We have relaxin receptors throughout our autonomic nervous system and brain, smooth muscle (which includes the blood vessels and arteries, and digestive tract), skin, and connective tissue. Perhaps its most principle role is to regulate the synthesis and maintainence of collagen, our primary connective tissue protein.Every part of our body and virtually every body function is thus affected or potentially influenced by relaxin. Muscle/tendon and ligament integrity, nerve conductivity, heart beat regularity, and even bone health all are positively affected by relaxin.

  3. Relaxin consists of two peptide chains, referred to as A and B, joined by disulfide bonds with an intra-chain disulfide loop in the A-chain in a manner analogous to that of insulin. The two human relaxin genes show considerable nucleotide and amino acid sequence homology to each other, however, there are some notable regions of sequence divergence, particularly in the amino-terminal region of both A- and B-chains.

  4. Alignment of Relaxin polypeptide chains • CLUSTAL W (1.81) multiple sequence alignment PDBSEQRES_3RLX_B -XSTNDFIKACGRELVRLWVE-ICGSVSTWGR PDBSEQRES_2RLX_B -XSTNDFIKACGRELVRLWVE-ICGSVSTWGR PDBSEQRES_1RLX_B -XSTNDFIKACGRELVRLWVE-ICGSVSTWGR PDBSEQRES_4RLX_B -XSTNDFIKACGRELVRLWVE-ICGSVSTWGR PDBSEQRES_6RLX_D -SWMEEVIKLCGRELVRAQIA-ICG-MSTWS- PDBSEQRES_6RLX_B -SWMEEVIKLCGRELVRAQIA-ICG-MSTWS- PDBSEQRES_6RLX_A XLYSALANKCCHVGCTKRSLARFC-------- PDBSEQRES_6RLX_C XLYSALANKCCHVGCTKRSLARFC-------- PDBSEQRES_4RLX_A --RMTLSEKCCQVGCIRKDIARLC-------- PDBSEQRES_3RLX_A --RMTLSEKCCQVGCIRKDIARLC-------- PDBSEQRES_2RLX_A --RMTLSEKCCQVGCIRKDIARLC-------- PDBSEQRES_1RLX_A --RMTLSEKCCQVGCIRKDIARLC--------

  5. Fibromyalgia Syndrome The diagnosis for FMS involves: - Widespread and often mobile sites of pain that has persisted for more than 3 months - 11 of the 18 tender point sites are painful with pressure Other associated symptoms can include, but are not limited to, digestive system problems (diarrhea/constipation and food allergies), profound fatigue, depression, and ‘Fibro-Fog’ (which is often described as a mental haziness and a loss of that mental edge). The common, unifying, and perhaps the most distressing symptom though, is the underlying pain. Relaxin: Promising Answers: - Dr. Samuel K. Yue has specialized in the care and management of patients with chronic and often debilitating pain. About 6 years ago his observations and insights gained from working with FMS patients led him to recognize the connection between a deficiency of the hormone relaxin and FMS. Hypothesis: A relaxin hormone deficiency is the fundamental cause of FMS and replacing or supplementing with relaxin is necessary to resolve the syndrome.

  6. 1-rhRlx 1-rhRlx is pro-angiogenic, stimulating new blood vessel growth in selective target tissues, such as the endometrial lining of the uterus (Dallenbach et al., 1966) and at ischemic wound sites (Unemori et al., in press). rhRlx stimulates the expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), potent angiogenic factors that can synergize to stimulate new blood vessel formation (Asahara et al., 1995), in endometrial stromal cells (Unemori et al., 1996), wound cells (Unemori et al., in press), and cells of the heart (Lewis et al., submitted).

  7. 2-rhRlx 2-rhRlx stimulates vasodilation of vascular beds. rhRlx causes vasodilation by activation of the endothelin B receptor subtype (Danielson et al., 2000) and stimulation of nitric oxide (Bani-Sacchi et al., 1995; Danielson et al., 1999). rhRlx also inhibits the vasoconstrictive effects of angiotensin II (Danielson et al., 1999; Massicote et al., 1989). There is evidence that it stimulates the production of atrial natriuretic peptide, as well (Toth et al., 1996).

  8. 3-rhRlx 3-rhRlx is anti-fibrotic, favoring the degradation of connective tissue, particularly under conditions of fibrosis. rhRlx acts as an anti-fibrotic agent by three distinct and additive pathways: (i) rhRlx directly decreases collagen production; (ii) it increases expression of collagenase, the enzyme that breaks down collagen; and (iii) it reduces the production of the major collagenase inhibitor, known as TIMP (Strutz et al., 1999; McDonald et al., 1999; Williams et al., 1999; Unemori et al., 1992; Unemori et al., 1990). rhRlx also mediates the elasticity of tissue (Kibblewhite et al., 1992).

  9. 3D Structure

  10. Transmembrane segments from GREASE for 6RLX PREDICTED TRANSMEMBRANE SEGMENTS TM 1: 5 - 31 (27)

  11. 3D Ribbon 6RLX 6RLX

  12. 1RLX

  13. The structure of relaxin has apparently diverged considerably among species during evolution. Only 40% to 48% amino acid sequence homology exists among porcine, rat, shark, and human relaxins.

  14. CLUSTALW Alignment • LNFEEFKKIILNRQNEAEDKSLLELKNLGLDKHSRKKRLFRMTLSEKCCQVGCIRKDIARLC • LNFEEFKKIILNRQNEAEDKSLLELKNLGLDKHSRKKRLFRMTLSEKCCQVGCIRKDIARLC • LNFEEFKKIILNRQNEAEDKSLLELKNLGLDKHSRKKRLFRMTLSEKCCQVGCIRKDIARLC • -----------------------------------------------------------------------------RMTLSEKCCQVGCIRKDIARLC • -----------------------------------------------------------------------------RMTLSEKCCQVGCIRKDIARLC • -----------------------------------------------------------------------------RMTLSEKCCQVGCIRKDIARLC • -----------------------------------------------------------------------------RMTLSEKCCQVGCIRKDIARLC • -----------------------------------------------------------------------------RMTLSEKCCQVGCIRKDIARLC********************** 1. HORMONE (MUSCLE RELAXANT) 2. relaxin chain A - Dall's porpoise, 22 AA 3. p2001.2 (4) RELX(3) // RELAXIN HORMONE FAMILY INSULIN CHAIN R-II1 PRECURSOR SIGNAL 3D-STRUCTURE, 23 AA 4. relaxin - Bryde's whale (fragments), 54 AA 5. relaxin - minke whale (fragments), 54 AA 6. Porcine relaxin gene, complete cds_ relaxin. AAA31115.1 [J02792], 182 AA 7. preprorelaxin [Sus scrofa] CAA01326.1 [A17335], 182 AA 8. relaxin precursor - pig, 182 AA

  15. CLUSTALW Alignment SDSCNR_493229 ------------------------XSTNDFIKACGRELVRLWVEICGSVSTWGR------ SDSCNR_691507 ------------------------QSTNDFIKACGRELVRLWVEICGSVSTWGR------ SDSCNR_199374 MPRLFSYLLGVWLLLSQLPREIPGQSTNDFIKACGRELVRLWVEICGSVS-WGRTALSLE SDSCNR_612835 ------------------------QKPDDVIKACGRELARLRIEICGSLS-WKQ------ SDSCNR_501797 -------------------------TDDKKLKACGRDYVRLQIEVCGS-SWWGRKAGQLR SDSCNR_612834 -----------------------DSWKDDVIKLCGRELVRAQIAICG-MSTWSKRSLQLY SDSCNR_362990 ------------------------GFLDKVIKVCGRDLVRIKIDICGKILLGDMTTGQEK SDSCNR:493229 HORMONE (MUSCLE RELAXANT)_Relaxin (theoretical model), 30 AA SDSCNR:691507 relaxin (theoretical model), chain B - pig, 30 AA SDSCNR:199374 Porcine relaxin gene, complete cds_ relaxin. AAA31115.1 [J02792], 182 AA SDSCNR:612835 relaxin - horse (fragments), 48 AA SDSCNR:501797 relaxin - dog (fragments), 59 AA SDSCNR:612834 relaxin - gorilla (fragments), 57 AA SDSCNR:362990 relaxin - guinea pig, 160 AA

  16. Chromosome 9 9pter-q12 relaxin 2 (H1 &H2)

More Related