Membrane lipids play diverse roles in cellular function. On the membrane, they act as structural elements, serve as a pool of secondary messengers and act as a platform for membrane proteins. 

Phosphatidyinositol (PI) plays an important role in signal transduction and membrane trafficking. The PI on the plasma membrane is phosphorylated to P1 and P2 which are an important substrate for Phospholipase C (PLC) mediated signaling (Bruce A Hamilton et al 1997).

The phosphatidyinositol levels need to be maintained in the plasma membrane for normal cellular signaling. The transportation of newly synthesized lipids to membrane is achieved by two mechanisms (1) Vesicular transport between membrane compartments (2) Use of carrier proteins for transportation [Shamshad Cockcrof et al 2007].

Phosphatidyinositol transfer proteins (PITPs) are lipid carrier proteins that balance the membrane lipid concentration by shuttling the phospholipids between various compartments. PITPs extract a molecule of PI from the membrane, sequester PI in its hydrophobic cavity and deposit it in the lipid membrane.

PITPs bind to PI and PC and transfer them between membrane compartments.
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The transport of lipids involves the following states: (i) Membrane Recognition (ii) Closed-open state transition (iii) Exchange of bound lipid (iv) Open-closed state transition and (v) Removal of the protein from the membrane. The open, closed and phosphorylated states of PITPα regulate its activity in the cell.

In mammals, the deficiencies of PITPs have led to intestinal malabsorption diseases, glucose homeostasis and neurodegenerative disorders [Bruce A Hamilton et al 2007]. PITPs are also important for the maintenance of mycelial growth programs in yeasts involved in pathogenesis [Vytas A Bankaitis et al 2005].

Similarly, in plants PITPs are involved in interesting developmental pathways that influence the biogenesis of the polarized membranes that play a role in nitrogen fixation and plant stress response [Sheri M Routt and Vytas A Bankaitis et al 2004]. 

Detailed understanding on structural features of transient intermediates of PITPs during lipid exchange would further shed light on the molecular details of loading-unloading of the lipid from the pocket. But it is difficult to obtain the structural feature of a short lived intermediate. 

NMR spectroscopy can be used for the structure determination of the low abundance intermediates. Various models have also been proposed elucidating the role of C-terminus region of PITPα in the transfer process.

So mutational analysis of the hydrophobic amino acids will provide more mechanistic insights into the transfer mechanism. The shuttling between open and closed conformation of PITPs is vital for the transport of the lipids to the plasma membrane.

NMR spectroscopy of isotope and spin labelled samples of PITPs can be used to investigate the occurrence of equilibria between open and closed conformation, both in the presence and absence of the membranes.

So, the structure and dynamics of the PITPs will help us to better understand the molecular basis of diseases as well as development of novel drugs against them.

Workflow and Implications

During the signal transduction the PI is further degraded as secondary messengers and therefore needs to be continuously replenished for proper cellular functions. 

This is achieved by continuously shuttling the newly synthesized PI lipids from endoplasmic reticulum (ER) to plasma membrane (PM). 

Phosphatidyinositol transfer proteins (PITPs) are a class of proteins that bind PI lipids and facilitate their transfer between different cellular membrane compartments. 

The transfer of lipids by PITPs includes several crucial steps including membrane binding/unbinding and shuttling between open and close conformations which are yet to be fully understood.

Moreover, these proteins are well conserved among all the organisms including mammals, Caenorhabditis elegans and Drosophila melanogaster. 

Further, several neurodegenerative diseases were reported to be associated with the dysfunction of PITPs. Therefore, it is important to decipher the crucial steps in lipid transfer by PITP and its transient conformations on the lipid membrane to delineate the structural basis for these neurodegenerative disorders. Similarly, structures of several closely related PITP homologues are yet to be revealed.


Asha Guraka

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