The invention provides methods and compositions for modeling and detecting LDL receptor transmembrane signaling by detecting proteolysis of an LDL receptor transmembrane domain. The method comprises the steps of: a) providing a sample comprising a cell membrane comprising (i) a polypeptide comprising an LDL receptor transmembrane domain fused to a C-terminal tail, and (ii) a protease which specifically cleaves the domain and thereby releases the tail from the membrane; b) incubating the sample under conditions wherein the protease cleaves the domain and thereby releases the tail from the membrane; and c) detecting a resultant released tail.