Transcript Overview of relaxin

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)].
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.
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.
Alignment of Relaxin polypeptide
chains
• CLUSTAL W (1.81)
PDBSEQRES_3RLX_B
PDBSEQRES_2RLX_B
PDBSEQRES_1RLX_B
PDBSEQRES_4RLX_B
PDBSEQRES_6RLX_D
PDBSEQRES_6RLX_B
PDBSEQRES_6RLX_A
PDBSEQRES_6RLX_C
PDBSEQRES_4RLX_A
PDBSEQRES_3RLX_A
PDBSEQRES_2RLX_A
PDBSEQRES_1RLX_A
multiple sequence alignment
-XSTNDFIKACGRELVRLWVE-ICGSVSTWGR
-XSTNDFIKACGRELVRLWVE-ICGSVSTWGR
-XSTNDFIKACGRELVRLWVE-ICGSVSTWGR
-XSTNDFIKACGRELVRLWVE-ICGSVSTWGR
-SWMEEVIKLCGRELVRAQIA-ICG-MSTWS-SWMEEVIKLCGRELVRAQIA-ICG-MSTWSXLYSALANKCCHVGCTKRSLARFC-------XLYSALANKCCHVGCTKRSLARFC---------RMTLSEKCCQVGCIRKDIARLC---------RMTLSEKCCQVGCIRKDIARLC---------RMTLSEKCCQVGCIRKDIARLC---------RMTLSEKCCQVGCIRKDIARLC--------
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.
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).
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 (BaniSacchi 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).
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).
3D Structure
Transmembrane segments from GREASE for 6RLX
PREDICTED TRANSMEMBRANE SEGMENTS TM 1: 5 - 31 (27)
3D Ribbon 6RLX
6RLX
1RLX
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.
CLUSTALW Alignment
1.
2.
3.
4.
5.
6.
7.
8.
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 3DSTRUCTURE, 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
CLUSTALW Alignment
SDSCNR_493229
SDSCNR_691507
SDSCNR_199374
SDSCNR_612835
SDSCNR_501797
SDSCNR_612834
SDSCNR_362990
------------------------XSTNDFIKACGRELVRLWVEICGSVSTWGR-----------------------------QSTNDFIKACGRELVRLWVEICGSVSTWGR-----MPRLFSYLLGVWLLLSQLPREIPGQSTNDFIKACGRELVRLWVEICGSVS-WGRTALSLE
------------------------QKPDDVIKACGRELARLRIEICGSLS-WKQ------------------------------TDDKKLKACGRDYVRLQIEVCGS-SWWGRKAGQLR
-----------------------DSWKDDVIKLCGRELVRAQIAICG-MSTWSKRSLQLY
------------------------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
Chromosome 9
9pter-q12 relaxin 2 (H1 &H2)