NEW YORK, Jan. 17, 2018 /PRNewswire-USNewswire/ -- A
new study reveals the molecular structure of a protein called
alpha(α)Klotho, and how it helps to transmit a hormonal signal that
slows aging.
Led by researchers from NYU School of Medicine and published
online Jan. 17 in Nature, the
study refutes 20 years of conjecture that αKlotho – named after the
Greek goddess who spins the thread of life – is a major anti-aging
hormone. Instead the results attribute this function to fibroblast
growth factor 23 (FGF23), and explain how αKlotho simply helps
FGF23 to mediate its anti-aging action.
Studies as far back as 1997 had shown that mice genetically
manipulated to lack either αKlotho or FGF23 suffered from premature
aging, including early onset cardiovascular disease, cancer, and
cognitive decline. By providing a first look at the structure of
the associated group of proteins that includes FGF23, its receptor
protein (FGFR), and αKlotho, the current study overturns the dogma
that αKlotho acts on its own as a longevity factor.
"By showing that all the ways in which αKlotho was supposed to
protect organs come instead from its ability to help FGF23 signal,
we have shed new light on the underlying cause of aging," says lead
study author Moosa Mohammadi, PhD,
professor in the Department of Biochemistry and Molecular
Pharmacology at NYU Langone Health. "Our new structural data also
pave the way for the design of novel agents that can either
encourage or block FGF23-αKlotho signaling as needed."
Structure Solves Mystery
To determine the atomic structure of the FGF23 signaling group
of proteins, Mohammadi and colleagues used X-ray crystallography.
The team first coaxed the FGF23 hormone, along with its receptor
protein (FGFR) and αKlotho, to settle out of a solution and form
stacks of repeating, orderly crystals. They then exposed the
crystals to X-rays, and used the reflected patterns to compute the
atomic structure of the proteins.
The new study provides the first evidence of how FGF23 can only
signal to cells by forming a complex with αKlotho, its receptor,
and another partner in heparan sulfate. Made by bone cells, the
FGF23 hormone is known to travel via the blood stream to cells in
other organs, where it delivers its message by docking onto and
turning on its receptor. The newly solved complex structure reveals
how αKlotho tethers FGF23 to its receptor with enough tenacity to
activate it.
The study also sheds new light on how kidney disease leads to an
abnormal thickening of heart muscle tissue called hypertrophy.
Heart hypertrophy is a leading cause of death in people with
damaged kidney tubules, caused (for example) by high blood pressure
and diabetes. When damaged kidney tubules can no longer adequately
eliminate phosphate in the urine, FGF23 rises in an effort to keep
blood phosphate in check, in part by controlling levels of vitamin
D. A prevailing hypothesis has been that very high levels of FGF23
cause hypertrophy in the heart, but the theory remained
controversial because heart tissue does not have αKlotho, which
must be present if FGF23 is to signal.
Past studies had shown that the best known form of αKlotho is
immobile, being bound to the surface membranes of cells in kidney
tubules, the parathyroid gland, and certain regions of the brain.
Then researchers learned that a part of the αKlotho protein that
protrudes from cell surfaces, the ecto domain, can be cut off and
shed into circulating bodily fluids, and therefore might reach the
heart. Early evidence, however, suggested that shed αKlotho was
incapable of acting as an FGF23 co-receptor. The new study
integrates these observations by showing that circulating αKlotho
can indeed function just like its membrane-bound form to enable
FGF23 signaling.
The researchers say that their findings will launch another drug
development race in kidney disease. Mohammadi had already shown
that a key piece of the FGF23 hormone (its C-terminal tail
peptide), when injected into mice, competes with intact FGF23 to
reduce its signal and prevent heart hypertrophy. In addition, the
team is already designing new molecules that alter the FGF23/shed
αKlotho signal based on the newly discovered protein
structures.
The study also suggests that a related protein, beta(b)Klotho,
serves as the same kind of co-receptor to help FGF21, a hormone
related to FGF23. FGF21 functions by sending signals that keep
blood sugar and fatty acids in balance, with implications for
diabetes and obesity.
Along with lead author Moosa
Mohammadi, the study authors from NYU Langone Health were
Gaozhi Chen, Yang Liu, Regina Goetz, and Lili
Fu. Other study authors were Seetharaman Jayaraman (New York Structural
Biology Center), Ming-Chang Hu and
Orson Moe (University of Texas Southwestern Medical Center,
Dallas); as well as Guang Liang and Xiaokun
Li (Chemical Biology Research Center at Wenzhou Medical
University, Zhejiang, China).
This work was primarily supported by National Institute of
Health (NIH) grant R01 DE13686. Funding was also provided through
National Key R&D Program of China grant 2017YFA0506000, NIH grants R01
DK092461, P30 DK079328, R01 DK09139, and the Beamlines Northeastern
Collaborative Access Team Facility at the Advanced Photon Source of
Argonne National Laboratory.
CONTACT: Gregory Williams,
212-404-3500, gregory.williams@nyumc.org
View original content with
multimedia:http://www.prnewswire.com/news-releases/researchers-discover-structure-of-anti-aging-hormone-300584084.html
SOURCE NYU Langone Health