The human immunodeficiency virus (HIV) remains a global health concern. Resistance and intolerance to current treatment demonstrates the need for novel therapeutics, but development of new therapies has been limited by the absence of a suitable animal model. Because replication of the feline immunodeficiency virus (FIV) is similar to that of HIV, felines offer potential as laboratory models for HIV. The viral matrix protein (MA) mediates assembly of the Gag polyprotein to the plasma membrane, a process common to both viruses for which no therapies are commercially available. Better understanding the structure of FIV MA would lend to our knowledge of FIV molecular biology and facilitate the use of cats as models for therapies against viral assembly.

N-terminal myristoylation of MA is critical for viral assembly on the cellular membrane. Myristoylation is facilitated by N-myristoyltransferase (NMT) which recognizes the myristoylation signal of MA and links the myristate to MA's amino- terminus. Interestingly, feline proteins follow the prototypical mammalian NMT recognition sequence while FIV MAs employ a unique signal. To identify structural and functional causes for this preference toward a non-consensus sequence, mutations were engineered to FIV MA such that the consensus feline myristoylation motif was incorporated. Myristoylation efficiency decreased upon adoption of this signal, thus structural studies were expanded from the myristoylated FIV MA (FIV myrMA) to also include the unmyristoylated FIV MA (FIV unmyrMA) and FIV unmyrMA using the consensus feline myristoylation signal (FIV unmyrMA G4L/Q5K/G6S).

The structure of FIV myrMA is similar to that of the HIV-1 myrMA and allowed for identification of residues within the protein core that support myristoyl sequestration. Analysis of FIV unmyrMA was initiated in order to understand the structure of FIV MA that is successfully recognized by NMT. These studies revealed that the NMT recognition sequence is unstructured. Contrastingly, FIV unmyrMA G4L/Q5K/G6S includes an amino-terminus that is more structured than the wild-type protein, a feature which appears to hinder NMT activity. Taken together, these studies indicate that FIV MA may prefer the unique, native sequence because it is efficiently myristoylated and better suited to support virus assembly.