Heart muscle is activated by ionized calcium, with the signaling pathway utilising allosteric mechanisms in the thin filament. Knowledge about the structure-function relationship among proteins in this filament is critical in understanding the physiology and pathology of the cardiac function and disease; however it remains obscure. Now, researchers at UT Southwestern have identified a previously unknown protein, which they have named DWORF, in human heart cells that plays a key role in heart muscle contraction. The team state their findings offer a potential new target for developing therapeutics to boost the strength of cardiac muscle contractions in patients with heart failure, a chronic condition in which the heart pumps too weakly to supply adequate oxygen to the body.
Previous studies show that a class of RNA transcripts has been dismissed as non-coding RNA, sometimes colloquially called ‘junk’ RNA. Emerging evidence, however, indicates that many small proteins with bioactive properties are hidden among these regions of the genome that are thought to be non-coding and, due to their small size, have evaded detection by scientists. The current study shows that the new protein, DWORF, is made from an RNA that was previously believed to be non-coding RNA, suggesting there may be many other small ‘non-coding’ segments that play important biological roles.
The current study shows that DWORF comprises just 34 amino acids, making it the third smallest protein known to be encoded in the mouse genome; by comparison, an average-sized protein is 10 times larger, including about 350 amino acids. Results show that DWORF is also encoded in the human genome.
Data findings show that the DWORF protein stimulates a calcium-ion pump that controls muscle contraction. Results show that as DWORF increases, the heart pumps with more force. The lab state that there’s a brake in the heart that controls pumping, and DWORF shuts off the brake, which has the effect of making heart muscle pump more vigorously. The group also identified DWORF in some skeletal muscle, namely slow-twitch skeletal muscle fibers, the type of muscle fiber that allows a person to run marathons.
The team surmise their data shows that although small and non-enzymatic themselves, peptides such as DWORF have the ability to regulate the function of much larger molecular complexes, analogous to the way that a tiny rudder determines the direction of a much larger ship. For the future, the researchers state that elucidating the full catalog of small proteins like DWORF could provide significant new insight into how the molecular machinery of the cell is regulated.
Source: UT Southwestern Medical Center