Dissecting the structure of titin kinase, to understand its vital role in cardiomyopathy

Dissecting the activation mechanism of titin kinase by NMR spectroscopy

Cardiomyopathies are diseases that affect the heart muscle and can cause heart failure. They may run in families due to genetic mutations that disrupt the contraction of heart muscle cells, which can impact the forceful pumping action of the heart. An important sensor of force generation in heart cells is located in one segment of a very large molecule called titin. There are already several known mutations in titin that lead to cardiomyopathies. The job of this sensor, called titin kinase (TK), is to ensure that other molecules are made quickly enough to respond to wear and tear in the cell. The harder the heart works, the more molecules are made, and vice versa. TK controls this production by binding to particular partners. We don’t yet know how that binding takes place, because TK’s structure is changeable depending on how much force the heart generates. New technology will now allow Dr Mark Pfuhl and his team to study the different structural versions of TK. This will reveal a fuller picture of how TK works and how it can go wrong in cardiomyopathies - and may help the development of therapies to treat these conditions.