RESEARCH: CANCER
FOLDING PROJECT #17906 PROFILE

This project studies how proteins called acyltransferases recognize different molecules. These proteins have a flexible loop that changes shape when they bind to a molecule, helping them become specialized. By looking at how these loops move, scientists hope to understand how proteins evolve to recognize specific targets without needing identical building blocks.

Understanding the molecular basis of substrate specificity for a given protein family is fundamental for the biophysical study of any metabolic process and related molecule design.

In this project, we model the apo and holo dynamics of acyltransferase enzymes demonstrating variable substrate specificity and organismal evolutionary stage.

Human acyltransferase activity is generally implicated in gene expression and cancer development.

Averaging ~18-25 sequence identity within their family, our selected acyltransferase enzymes maintain a remarkably conserved topology, where the front and back domains of these proteins form a doughnut-like shape bridged by an ~50 residue intrinsically disordered loop (IDL).

Sequence-based analyses suggest that some correlation exists between the extent of disorder in this IDL region and the extent of demonstrated substrate permissiveness by the respective enzyme.

By comparing loop dynamics in response to substrate recognition between the different modeled proteins, our goal is to offer fundamental insights into how soluble proteins can evolve substrate specificity without converging to a conserved amino acid sequence.

substrate

A substance acted upon by an enzyme.

In biochemistry, a substrate is the molecule that an enzyme acts upon to catalyze a chemical reaction. Enzymes are proteins that speed up these reactions by binding to substrates and lowering the activation energy required for the reaction to occur.

acyltransferase

An enzyme that catalyzes the transfer of an acyl group (e.g., fatty acid) from one molecule to another.

Acyltransferases are a crucial class of enzymes involved in various metabolic processes. They facilitate the transfer of acyl groups, such as fatty acids, from one molecule to another. These reactions play vital roles in lipid metabolism, signal transduction, and protein modification.

protein family

A group of proteins that share a common evolutionary origin and structural/functional similarities.

Proteins belonging to the same family often exhibit conserved domains, motifs, and overall structures. This shared ancestry reflects their functional relatedness and suggests that they may have evolved from a common ancestral protein.

topology

The overall three-dimensional arrangement of atoms or subunits in a molecule.

In the context of proteins, topology refers to their spatial arrangement. It describes how different parts of the protein chain are connected and folded into specific shapes. Understanding protein topology is crucial for comprehending their function and interactions.

intrinsically disordered loop (IDL)

Intrinsically Disordered Loop

An intrinsically disordered loop (IDL) is a region within a protein that lacks a defined three-dimensional structure. These loops are often flexible and play important roles in protein function, such as binding to other molecules or mediating interactions.