Cloth (protein)

Clotho
Properties of human protein
Mass / length primary structure	not exactly known
Precursor	(979 aa)
Identifier
Gene name	KL
External IDs	OMIM : 604824 ; UniProt : Q9UEF7 ;
Occurrence
Parent taxon	Vertebrates

Klotho is a proteohormone thatcan extend the life of mice by around 20 to 30%.

In 1997 Makoto Kuro'o identified a new gene at the National Institute for Neuroscience in Tokyo, which extends the lifespan of the mouse when it is expressed in high levels . A defect in this gene results in a syndrome that is similar to human aging. The affected animals have a reduced life expectancy , are sterile and develop typical age-related diseases such as arteriosclerosis , skin atrophy , osteoporosis and pulmonary emphysema .

The Klotho gene codes for a transmembrane protein with a transmembrane domain . The Klotho protein binds as a co-receptor to various receptors for fibroblast growth factor (Fibroblast Growth Factor) . So far, 22 fibroblast growth factors are known, but only four different receptors. It is therefore assumed that the specificity of the receptor proteins is mediated by co-receptors. Only the binding of Klotho to fibroblast growth factor receptor 1 ( FGFR1 subtype IIIc ) leads to the fact that fibroblast growth factor 23 (FGF23) can specifically bind. FGF23 is a bone hormone that inhibits the reabsorption of phosphate and the synthesis of vitamin D in the kidneys . Mice treated with a monoclonal antibody against Klotho no longer respond to FGF23.

In the kidney

Klotho inhibits the reabsorption of phosphate in the proximal tubular cells through direct binding to the FGF receptor,
Klotho regulates calcium reabsorption by stabilizing the TRPV5 calcium channel in the cell membrane,
Klotho inhibits 1α-hydroxylase and thus the activation of 25 (OH) vitamin D3 to calcitriol .

The effect on calcium and phosphate transport in the kidneys is synergistic to the effects of parathyroid hormone , while the effect on calcitriol synthesis is antagonistic .

The extracellular domain of Klotho is split off and thus becomes a humoral factor. The secreted Klotho protein regulates several signaling pathways, including the insulin / IGF-1 pathway and the Wnt signaling pathway , as well as the activity of many ion channels . In addition, the Klotho protein protects cells and tissue from oxidative stress , but the exact mechanism has not yet been clarified.

Mice with a defect in the gene for FGF23 are very similar to mice with a defect in the Klotho gene.

Knockout mice for FGF23 and Klotho show multiple defects:

decreased life span
decreased sexual maturity with infertility
Kyphosis
arteriosclerosis
extensive soft tissue calcifications
Atrophy of the skin
muscular dystrophy
disturbed T cell function
Emphysema
Osteopenia
disturbed mineral -Household, in particular calcium - phosphate -Household
impaired vitamin D metabolism.

Because of these changes, there is currently much speculation about a close connection between aging of the vascular system, vitamin D and the phosphate balance.

In 2007, a homozygous mutation of the Klotho gene was described for the first time in humans . A 13-year-old girl was affected who developed severe calcinosis ( Teutschländer's disease ) with calcifications of the common carotid artery and the outer meninges (dura mater) . Disturbances in the mineral metabolism with increased serum phosphate , increased serum calcium , increased parathyroid hormone and increased FGF23 were found. Expression and secretion of Klotho were significantly reduced, which led to a restricted signal transmission of FGF23 via the FGF23 receptor.

Web links

Tumor calcinosis. In: Online Mendelian Inheritance in Man . (English).
FGF signaling: Ligand specificity uncovered Illustration of the Klotho / FGFR1 / FGF23 complex on Featured articles: December 2006 of the Nature Publishing Group
de Bono / Mohammadi / reactome: FGFR1c and Klotho ligand binding and activation

Individual evidence

↑ Homologues at OMA
↑ M. Kuro-o et al .: Mutation of the mouse klotho gene leads to a syndrome resembling aging . In: Nature . No. 390 , 1997, pp. 45-51 , PMID 9363890 ( nature.com ).
↑ Shiguang Liu, L. Darryl Quarles: How Fibroblast Growth Factor 23 Works . In: J Am Soc Nephrol . No. 18 , 2007, p. 1637-1647 ( asnjournals.org ).
^ I Urakawa et al .: Klotho converts canonical FGF receptor into a specific receptor for FGF23 . In: Nature . No. 444 , 2006, pp. 770-774 , PMID 17086194 .
↑ ^a ^b TB Drüeke, D Prié: Klotho spins the thread of life - what does Klotho do to the receptors of fibroblast growth factor-23 (FGF23)? In: Nephrol Dial Transplant . No. 22 , 2007, p. 1524-1526 ( oxfordjournals.org ).
↑ ^a ^b Kuro-o M: Klotho as a regulator of oxidative stress and senescence . In: Biol Chem . No. 389 (3) , 2008, pp. 233-241 , PMID 18177265 .
↑ S. Ichikawa et al .: A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis . In: J Clin Invest. No. 117 (9) , 2007, pp. 2684-2691 , PMID 17710231 ( jci.org ).

[1] Homologues at OMA

[Kuro-o-2] M. Kuro-o et al .: Mutation of the mouse klotho gene leads to a syndrome resembling aging . In: Nature . No. 390 , 1997, pp. 45-51 , PMID 9363890 ( nature.com ).

[Liu,Quarles-3] Shiguang Liu, L. Darryl Quarles: How Fibroblast Growth Factor 23 Works . In: J Am Soc Nephrol . No. 18 , 2007, p. 1637-1647 ( asnjournals.org ).

[Urakawa-4] I Urakawa et al .: Klotho converts canonical FGF receptor into a specific receptor for FGF23 . In: Nature . No. 444 , 2006, pp. 770-774 , PMID 17086194 .

[Drüeke2007-5] TB Drüeke, D Prié: Klotho spins the thread of life - what does Klotho do to the receptors of fibroblast growth factor-23 (FGF23)? In: Nephrol Dial Transplant . No. 22 , 2007, p. 1524-1526 ( oxfordjournals.org ).

[Kuro-o2008-6] Kuro-o M: Klotho as a regulator of oxidative stress and senescence . In: Biol Chem . No. 389 (3) , 2008, pp. 233-241 , PMID 18177265 .

[Ichikawa-7] S. Ichikawa et al .: A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis . In: J Clin Invest. No. 117 (9) , 2007, pp. 2684-2691 , PMID 17710231 ( jci.org ).