Journal News

Decoding a protein’s role in connective tissue disorders

Nicole Lynn
Aug. 18, 2020

Composed of proteins, fibers, cells and other substances, connective tissues attach, stabilize and reinforce the structure of human bodies. While there are many causes of connective tissue disorders, Ehlers–Danlos syndrome, or EDS, involves the disruption of collagen or collagen-regulating proteins by means of genetic mutations.

EDS, which affects as many as one in 2,500 people, is an inherited disorder that weakens connective tissues, specifically affecting the skin, joints and blood vessels. Researchers recently have found that some EDS-presenting families share mutations in the adipocyte enhancer binding protein 1, or AEBP1, gene, which encodes for the aortic carboxypeptidase-like protein, or ACLP, found in collagen-rich connective tissues including the skin, ligaments, tendons and vasculature. Individuals with AEBP1 mutations develop a subtype of EDS called EDS-classic-like-2, or EDSCLL2, which is characterized by joint hypermobility, abnormal scarring, delayed wound healing and vascular ruptures.

Medical student Neya Vishwanath, then a second-year master’s student in the medical sciences program at the Boston University School of Medicine, and colleagues in Matthew Layne’s lab were interested in investigating mutations in AEBP1 and the processing mechanisms for ACLP. Their goal was to examine mechanisms of protein secretion and collagen fiber stability for these proteins in the context of EDS.

“In all my biology courses, we were always taught how integral connective tissue is to a healthy body,” Vishwanath said. “In the Layne lab, (we) wanted to better understand the importance of ACLP in connective tissue health and figure out how mutations in ACLP could cause human disease.”

ACLP-696x683.jpg
Layne Lab/JBC
This image shows 3T3 fibroblast cells transfected with wild-type aortic carboxypeptidase-like protein or tagged ACLP-Ins40. The mutated
protein leads to an apparent gap around the nucleus, potentially indicating an absence of intracellular trafficking to the Golgi.

In a recent paper in the Journal of Biological Chemistry, Vishwanath and colleagues highlight a specific mutation found in EDS patients called ACLP-Ins40. They found that this mutation, which causes an insertion of 40 amino acids in the collagen-binding region of ACLP, results in the improper exit of ACLP from cells and leads to cellular stress. The researchers also mapped and identified the specific amino acids required for proper ACLP secretion.

The team also identified novel protein processing mechanisms critical in ACLP secretion. Specifically, they demonstrated how glycosylation, or the addition of sugar groups to ACLP, is necessary for the proper cellular exit. When sugar groups are unattached to ACLP, the result is in-cell retention of ACLP and increased cellular stress.

Research with two other labs focused on the potential for ACLP to contribute to collagen fiber mechanics, specifically highlighting ACLP’s role in mechanical strength, Vishwanath said. “Our collaborative studies with Michael Smith and Joyce Wong’s laboratories at Boston University determined that ACLP contributes to the mechanical strength of collagen fibers that make up numerous connective tissues including ligaments, tendons, and cartilage.”

Vishwanath and her colleagues hope insights from this work will contribute to a greater understanding of the mechanisms involved in connective tissue structures and provide scientists with targets for pharmacological interventions to treat connective tissue disorders such as EDS.

Enjoy reading ASBMB Today?

Become a member to receive the print edition monthly and the digital edition weekly.

Learn more
Nicole Lynn

Nicole Lynn holds a Ph.D. from UCLA and is an ASBMB Today volunteer contributor.

Get the latest from ASBMB Today

Enter your email address, and we’ll send you a weekly email with recent articles, interviews and more.

Latest in Science

Science highlights or most popular articles

Iron could be key to treating a global parasitic disease
Journal News

Iron could be key to treating a global parasitic disease

April 16, 2024

A study has found that leishmaniasis causes body-wide changes in iron balance, leading to red blood cell damage.

Environmental DNA is everywhere
News

Environmental DNA is everywhere

April 14, 2024

The ability to extract trace bits of DNA from soil, water, and even air is revolutionizing science. Are there pitfalls?

Early COVID-19 research is riddled with poor methods and low-quality results
News

Early COVID-19 research is riddled with poor methods and low-quality results

April 13, 2024

The pandemic worsened, but didn’t create, this problem for science.

From the journals: MCP
Journal News

From the journals: MCP

April 12, 2024

Three views of mass spec: analyzing secreted protein spectra, imaging mass spectrometry for clinical use and spectral libraries for MS data analysis. Read about these recent papers.

Understanding the fat science
Journal News

Understanding the fat science

April 9, 2024

Researchers at UCLA investigate lipid remodeling in the liver for energy generation.

No oxygen? No problem
Journal News

No oxygen? No problem

April 8, 2024

By studying how electric fish survive in hypoxic streams for months at time, researchers may find new ways to target tumors.