New Study Uncovers Temperature-Driven Mechanism in Metamorphic Proteins
Dr. John Orban, IBBR Fellow and a Professor in the Department of Chemistry and Biochemistry at University of Maryland and his co-author Andy LiWang, a Professor of Chemistry and Biochemistry at the University of California, Merced, recently published a Perspectives article “Unveiling the cold reality of metamorphic proteins” in PNAS providing new insights on metamorphic proteins.
Metamorphic proteins, as their name suggests, are essentially shapeshifting proteins that can adopt more than one folded state. The two states are in equilibrium, but the underlying basis for this equilibrium is still poorly understood.
Orban and LiWang had previously studied two unrelated metamorphic proteins, the designed protein Sa1V90T, and the circadian clock protein KaiB, and noticed that they switched between states in response to temperature changes. More specifically, the lower-temperature states were more disordered with fewer hydrophobic contacts, while the higher-temperature states were more structured. This phenomenon is called cold-denaturation, where proteins can lose some or all of their structured folds at lower temperatures because of weakened hydrophobic interactions. Thus, the researchers were curious to see if other known metamorphic protein pairs exhibited similar temperature dependence.
26 metamorphic protein pairs were analyzed for hydrophobic contacts in their two states. Where there was relevant experimental data, they found the same pattern of fewer hydrophobic contacts in the lower temperature state and more contacts in the higher temperature state. This finding suggests that temperature-dependent changes in hydrophobicity may be an essential feature of many metamorphic proteins.
The researchers propose that the temperature trigger of metamorphic proteins may provide an adaptive or evolutionary advantage. For example, the protein KaiB found in ectotherms, being reliant on temperature changes, can help maintain accurate timekeeping as the environment changes. Orban and LiWang are further intrigued by how metamorphic proteins might have evolved in endotherms such as humans, where temperature is internally regulated.
This paper not only advances the current understanding of metamorphic proteins but also provides new insights for the prediction and design of these proteins. Modeling proteins is an important way to study them, and the consideration of temperature may play a vital role in improving modeling and prediction technologies. They plan to expand their analysis with a larger dataset of metamorphic proteins and further explore the potential of temperature in fold switching.
