Structural biology of moonlighting: lessons from antibodies

Protein moonlighting is the property of a number of proteins to have more than one function. However, the definition of moonlighting is somewhat imprecise with different interpretations of the phenomenon. True moonlighting occurs when an individual evolutionary protein domain has one well-accepted role and a secondary unrelated function. The ‘function’ of a protein domain can be defined at different levels. For example, although the function of an antibody variable fragment (Fv) could be described as ‘binding’, a more detailed definition would also specify the molecule to which the Fv region binds. Using this detailed definition, antibodies as a family are consummate moonlighters. However, individual antibodies do not moonlight; the multiple functions they exhibit (first binding a molecule and second triggering the immune response) are encoded in different domains and, in any case, are related in the sense that they are a part of what an antibody needs to do. Nonetheless, antibodies provide interesting lessons on the ability of proteins to evolve binding functions. Remarkably similar antibody sequences can bind completely different antigens, suggesting that evolving the ability to bind a protein can result from very subtle sequence changes.