Membrane proteins are structurally and functionally diverse groups of proteins whose activities are as versatile as transporters to immune recognition. Our earlier views regarding the organization of membrane proteins came from the fluid mosaic model. In this model two classes of membrane proteins were described viz. the integral membrane proteins (IMPs) which are linked to the membrane by one or more membrane spanning transmembrane peptides (TM) and the peripheral membrane proteins (PMPs), which remain loosely attached to the membrane. The IMPs are predicted to constitute 20-30% of the genomes of humans and other organisms. However, this estimation is biased in detecting only alpha helical TM segments and cannot predict other forms of membrane associations, such as covalent association or monotopic interaction with one of the bilayers of the membrane. Our current understanding regarding the organization and the distribution of membrane proteins has been limited for two main reasons viz. (i) the lack of technical platforms that address membrane specific issues such as the solubility and the dynamic ranges of proteins and (ii) inadequate knowledge regarding the individual protein components of the membrane. In the current study I have explored the possibility of parallel approaches in deciphering the membrane proteome and developed a novel, detergent free proteomic method for the global analysis of membrane proteins.;Integral membrane components were enriched from the isolated membranes using reagents that are known to remove loosely interacting membrane proteins. Proteomic investigation of the membranes indicated the existence of a subset of proteins which were not predicted or reported to have TM regions but exhibited strong resistance to conventional membrane stripping conditions similar to that of integral membrane proteins. These proteins are largely involved in cellular processes and molecular functions that could be predicted to be transiently associated with membranes. Evidence of novel GPI linked proteins was also provided in the current study. In essence, our results suggested that the membrane proteome is a dynamic structure involving interactions that may be time limited but very stable during the association period. This observation also highlighted the need for additional criteria in the definition of membrane proteins.
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