07/18/2025
By Kwok Fan Chow

The Kennedy College of Science, Department of Chemistry, invites you to attend a Ph.D. Dissertation defense by Sabrina Apel entitled “Biophysical Characterization of the Interaction Between S100A1 and Titin's UN2A Region.”

Degree: Doctoral
Location: Olney, Room 518
Date: Thursday, July 31, 2025
Time: 1 p.m.

Committee

  • Chair: Matthew Gage, Department of Chemistry, University of Massachusetts Lowell
  • Jeffrey R. Moore, Department of Biological Sciences, University of Massachusetts Lowell
  • Jin Xu, Department of Chemistry, University of Massachusetts Lowell
  • Juan Manuel Artes Vivancos, Scientific Department (Unit B4, Physical Sciences and Engineering), European Research Council Executive Agency

Abstract:
Titin, the largest known protein in the human body, spans half of the sarcomere and plays essential roles in muscle elasticity, active and passive force regulation, and mechanosensing, thereby maintaining sarcomere integrity in both cardiac and skeletal muscles. It is composed of multiple domains and repeated structural elements, including immunoglobulin-like (Ig) domains, fibronectin type III (FnIII) domains, and unique disordered regions. Together, these domains allow titin to act as a molecular spring, contributing to both the structural stability of the myofibril and the regulation of contraction and relaxation. Within titin’s I-band region, the N2A region is positioned between the proximal Ig domains and the PEVK region, and is composed of four Ig domains (Ig80-Ig83) and a unique 117-amino acid insertion sequence known as UN2A. This region has been identified as a potential signaling hub due to its involvement in multiple protein interactions required for normal muscle function. The N2A domains display calcium sensitivity, suggesting that calcium may modulate interactions involving this region during muscle activation. Given these characteristics, the N2A region was investigated as a potential binding site for calcium-binding regulatory proteins. S100A1, the most abundant S100 isoform in cardiac and skeletal muscle, is a key mediator of calcium signaling and is known to bind and regulate several targets, including the ryanodine receptor and titin’s PEVK region in its calcium-dependent manner. Preliminary sequence analysis of UN2A suggested the presence of a potential S100A1 binding site, prompting further investigation of this interaction. In this dissertation, I investigate (1) the calcium- and pH-dependent interaction between the UN2A region and S100A1, and (2) the contribution of specific disordered and structured regions of UN2A to its structural properties and binding behavior.

Based on the findings presented in this dissertation, I propose a model in which the UN2A region of titin acts as a calcium- and pH-responsive site that modulates its interaction with S100A1. This behavior appears to be supported by the conformational flexibility of UN2A, allowing it to adjust in response to changes in its biochemical environment. Through this mechanism, UN2A may influence titin extensibility and sarcomeric behavior under varying cellular conditions. These findings reveal a previously uncharacterized interaction between S100A1 and titin’s UN2A region, offering new insight into how titin responds to calcium, pH, and mechanical cues.

All interested students and faculty members are invited to attend.