Nav: Home

Choosing the right substrate for the right function

April 04, 2017

Scientists at Tokyo Institute of Technology have discovered a unique molecular mechanism responsible for the substrate preference of ubiquitin-specific proteases.

Ubiquitin is a small, highly conserved, eukaryotic regulatory protein that can be attached to Lys residues on intracellular proteins via isopeptide bonds. Ubiquitin can also be attached to one of seven Lys residues of other ubiquitin moieties forming poly-ubiquitin chains on target proteins. Depending on which Lys in ubiquitin is used to form poly-ubiquitin chains, distinct signaling functions take place. Thus, Lys48-linked polyubiquitination, which is the most abundant in the cell, results in proteasomal degradation of target proteins, whereas Lys63-linked polyubiquitination regulates multiple cell activities such as protein trafficking and DNA repair. Ubiquitination is reversible as the formed isopeptide bonds can be cleaved by deubiquitinating enzymes which sometimes exhibit different preferences for Lys48- and Lys63-linked ubiquitin chains. However, the molecular mechanisms underlying the substrate specificity of deubiquitinases toward Lys48-linked ubiquitin chains remain largely unknown.

Researchers at Tokyo Institute of Technology led by Professor Masayuki Komada addressed this problem by investigating the function of ubiquitin-specific protease (USP)25, which in this study was found to favor the Lys48 linkage for cleavage. USP25 contains two tandem ubiquitin-interacting motifs (UIMs) representing 20-amino-acid α-helices (Figure). To test whether UIM-mediated binding results in substrate preference, these scientists generated a panel of USP25 mutants carrying substitutions of functional amino acids in UIMs and analyzed their interaction with and catalytic activity toward Lys48- or Lys63-linked ubiquitin chains. It appeared that the tandem UIMs not only enhanced the isopeptidase activity of USP25 but also determined its preferential cleavage of Lys48-linked ubiquitin chains. Preferential binding of the UIMs to Lys48-linked ubiquitin chains seems to play a role, as swapping of the UIMs to those of other proteins with binding specificity for Lys48-linked chains significantly shifted USP25 preference from the Lys48 towards Lys63 linkage, suggesting the importance of UIM's ubiquitin chain-binding specificity for USP25's substrate specificity.

These findings present the first example of deubiquitinases in which the substrate preference toward Lys48-linked ubiquitin chains is determined by UIMs. The scientists suggest that UIMs play a role in the catalytic mechanism by keeping Lys48-linked ubiquitin chains in close proximity to the active site of the enzyme (Figure). Future structural studies of USP25 complexed with a Lys48-linked ubiquitin chain should determine whether this is indeed the case.
-end-


Tokyo Institute of Technology

Related Proteins Articles:

Discovering, counting, cataloguing proteins
Scientists describe a well-defined mitochondrial proteome in baker's yeast.
Interrogating proteins
Scientists from the University of Bristol have designed a new protein structure, and are using it to understand how protein structures are stabilized.
Ancient proteins studied in detail
How did protein interactions arise and how have they developed?
What can we learn from dinosaur proteins?
Researchers recently confirmed it is possible to extract proteins from 80-million-year-old dinosaur bones.
Relocation of proteins with a new nanobody tool
Researchers at the Biozentrum of the University of Basel have developed a new method by which proteins can be transported to a new location in a cell.
Proteins that can take the heat
Ancient proteins may offer clues on how to engineer proteins that can withstand the high temperatures required in industrial applications, according to new research published in the Proceedings of the National Academy of Sciences.
Designer proteins fold DNA
Florian Praetorius and Professor Hendrik Dietz of the Technical University of Munich have developed a new method that can be used to construct custom hybrid structures using DNA and proteins.
The proteins that domesticated our genomes
EPFL scientists have carried out a genomic and evolutionary study of a large and enigmatic family of human proteins, to demonstrate that it is responsible for harnessing the millions of transposable elements in the human genome.
Rare proteins collapse earlier
Some organisms are able to survive in hot springs, while others can only live at mild temperatures because their proteins aren't able to withstand such extreme heat.
How proteins reshape cell membranes
Small 'bubbles' frequently form on membranes of cells and are taken up into their interior.

Related Proteins Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Jumpstarting Creativity
Our greatest breakthroughs and triumphs have one thing in common: creativity. But how do you ignite it? And how do you rekindle it? This hour, TED speakers explore ideas on jumpstarting creativity. Guests include economist Tim Harford, producer Helen Marriage, artificial intelligence researcher Steve Engels, and behavioral scientist Marily Oppezzo.
Now Playing: Science for the People

#524 The Human Network
What does a network of humans look like and how does it work? How does information spread? How do decisions and opinions spread? What gets distorted as it moves through the network and why? This week we dig into the ins and outs of human networks with Matthew Jackson, Professor of Economics at Stanford University and author of the book "The Human Network: How Your Social Position Determines Your Power, Beliefs, and Behaviours".