Key result
Hydrogen-deuterium exchange mass spectrometry successfully mapped pepsin-derived mass fragments covering 94% of the SMTNL1-CH domain and 83% of a functional TM-binding truncate.
HXMS mapping of the SMTNL1-tropomyosin binding interface provides a structural framework for understanding its physiological role in vascular smooth muscle biology.
No immediate clinical implications for vascular disorders; leaves open SMTNL1-tropomyosin targeting for future mechanistic studies.
The smoothelin‐like 1 protein (SMTNL1) modulates muscle contractile activity, particularly in exercise adaptation. SMTNL1 bears sequence similarity to smoothelin, a smooth muscle differentiation marker, particularly in its calponin homology (CH) domain. The interaction of SMTNL1 with tropomyosin (TM) is dependent on the CH domain and some portion of a central, unfolded region (aa 197–342) of SMTNL1. These data are based on pull‐down studies with SMTNL1 truncations, and reinforced by isothermal titration calorimetry experiments. We hypothesize that independent sections of the SMTNL1 protein cooperate to form a functional TM binding surface. We will elucidate the specific surfaces of SMTNL1 involved in TM binding using hydrogen‐deuterium exchange mass spectroscopy (HXMS). To this end, we have mapped pepsin‐derived mass fragments covering 94% of the SMTNL1‐CH domain, and 83% of a functional TM‐binding truncate (SMTNL1‐∆N, aa 196–459). These maps will be compared with deuterated SMTNL1 samples, and with SMTNL1 samples deuterated while bound to TM. The deuterium incorporated is calculated for each SMTNL1 peptide to reveal the interaction interface. The objectives will address the molecular and structural elements of the SMTNL1‐TM interaction and provide a framework for the physiological role of SMTNL1 in vascular smooth muscle biology. The research was supported by HSFC and CIHR.
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Butler et al. (2010) studied this question. Hydrogen-deuterium exchange mass spectrometry (HXMS) was evaluated on Mapping of pepsin-derived mass fragments of SMTNL1. Hydrogen-deuterium exchange mass spectrometry successfully mapped pepsin-derived mass fragments covering 94% of the SMTNL1-CH domain and 83% of a functional TM-binding truncate.
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