Abstract 4548: Uncovering the membrane targeting mechanism of human unconventional class I myosins: a computational study

Abstract

Abstract The class 1 myosins (Myo1) are a widely expressed family of single-headed, non-filament-forming, membrane-binding myosins that comprise several sub-classes and are characterized by their ability to cross-link the plasma membrane to the underlying actin cytoskeleton by the presence of a lipid-binding region in the tail domain and an actin-binding region in the motor domain. Consequently, these motor proteins are drivers of numerous cellular processes that link the membranes to the actin cytoskeleton, including but not limited to vesicle trafficking, phagocytosis, cell migration, and intracellular membrane trafficking. Their importance in regulating these processes is underscored by studies that link pathogenesis and cancer with this class of motor proteins. For example, it has been recently shown that aberrant expression of Myo1b is linked to the lymph node metastasis of human head and neck squamous cell carcinoma through enhanced cancer cell motility and therefore, an interesting target for new diagnostic and therapeutic strategies for patients with this type of cancer, the sixth most common malignancy worldwide. Our focus in this study is the little studied aspect of membrane targeting in the different sub-classes for Myo1, even though it is critical part of the functionality of these proteins. Biological membranes are an intricate system consisting of many structurally discrete proteins and lipids that serve as interaction sites with lipid binding domains of soluble proteins. The pleckstrin homology (PH) domain is one of the most common structural folds that serve as a perfect scaffold for cytosolic proteins to bind and target membranes. Although conventional sequence analysis doesn’t identify any membrane binding domains in the tails of Myo1 proteins, recent studies of Myo1c and Myo1g implicate the presence of a PH domain and attribute this domain to their membrane targeting function. A preliminary analysis based on a combination of sequence analysis and secondary structure prediction tools, suggested that Myo1b and several other sub-classes also contain a PH domain. We hypothesize that the membrane targeting function of all Myo1 sub-classes is driven by the presence of a PH domain within their tails. To address this hypothesis, we have carried out a comprehensive investigation of the Myo1 tails from all human unconventional class I myosin isoforms sub-classes to identify, model, and analyze the membrane binding mechanism of their PH domains. This study details the membrane binding mechanisms of unconventional class I myosins and lays the foundation for the role of membrane targeting of Myo1 proteins in cancer and disease. Citation Format: Daniel Gruffat, Shaneen Singh. Uncovering the membrane targeting mechanism of human unconventional class I myosins: a computational study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4548. doi:10.1158/1538-7445.AM2017-4548