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Dr Amir Khan

X-Ray Crystallography

A. Khan photo

Dr Amir Khan
Associate Professor
Phone: +353-1-8963870
Fax: +353-1-6772400
Location: Room 5.54, Trinity Biomedical Sciences Institute

Our group was established in 2004 with support from the Higher Education Authority (through their PRTLI3 initiative), as well as a grant from Science Foundation Ireland. We are dedicated to exploring the molecular basis for biological processes in living cells. The main technique employed in our laboratory is X-ray diffraction, which allows visualization of the three-dimensional architecture of macromolecules.


View audio/video clip of Dr Khan talking about his research (mp4, 27.4MB)

There are two main projects underway in our laboratory. The first is a structural study of Rabs with their effector proteins, and the mechanism by which these complexes regulate vesicle trafficking. A second major initiative involves structural studies of Toll receptor signaling pathways, which are essential for innate immunity against bacteria and viruses.

The overall research goal is to provide insight into the specificity of signaling complexes, and how they lead to changes in cellular activity. To address these problems, our lab is fully equipped for protein expression, purification, crystallization and structure determination.

Structural basis for Rab-effector specificity and function

Cells are a dynamic system, requiring movement of vesicles between various membrane compartments.  Vesicles bear protein markers that efficiently target them to destinations such as Golgi, endoplasmic reticulum, endosomes and the plasma membrane.  The markers are a family of 70 Rab proteins that interact with partner 'effector' proteins to carry cargo efficiently within living cells.  Mutations in Rab proteins can lead to diseases like Griscelli's syndrome, resulting in immune dysfunction and blindness.  Each Rab specifically interacts with many protein partners, but the nature of these interactions and how they regulate traffic is not understood. 

Structure of Rab11-FIP2
Toward the goal of understanding vesicle transport at the molecular level, we have determined the crystal structures of Rab11 with one of its cognate effector proteins, FIP2. The small GTPase Rab11 regulates the recycling of endosomes to the plasma membrane via interactions with the Rab11 Family of Interacting Proteins (FIPs; reviewed by Prekeris, 2003). FIPs contain a highly conserved Rab-binding domain (RBD) at their C-termini whose structure is unknown. The crystal structure of the RBD of FIP2 in complex with Rab11(GTP) was determined by single wavelength anomalous diffraction methods (Jagoe et al., 2006). The overall structure is a hetero-tetramer with dyad symmetry, arranged as a Rab11-(FIP2) 2 -Rab11 complex. FIP2 forms a central a -helical coiled-coil, with both helices contributing to the Rab11 binding patch on equivalent and opposite sides of the homodimer. The C-terminal ‘tail' of the Rab11 molecules, which is tethered via prenylation to lipids, was deleted to facilitate crystallization. Switch 1 of Rab11 is embedded between the two helices, while switch 2 remains flexible and is peripherally associated with the effector. The complex reveals the structural basis for Rab11 recognition by FIPs, and we are continuing to investigate the mechanisms by which the complex regulates downstream recycling pathways.

Structure of Rab11-FIP2

Structure of Rab11-FIP2. The coiled coil of the centrally positioned effector (pink, green) recruits two Rab11 molecules on equivalent and opposite sides. The position of the plane of the membrane bilayer is shown for illustration only.







Prekeris R (2003) ScientificWorldJourna l 3: 870-880.
Jagoe N, Lindsay AJ, Read RJ, McCoy AJ, McCaffrey MW & Khan AR (2006) Structure 14: 1273-1283.

Structure of Rab6 in complex with Rab6-Interacting Protein 1
Rab6 regulates vesicular cargo at the level of Golgi via interactions with numerous and unrelated effector proteins (Bergbrede et al, 2009; Miserey-Lenkei, 2007). The crystal structure of Rab6a(GTP) in complex with a 378-residue internal fragment of the effector Rab6IP1 (Rab6 Interacting Protein 1) has been solved at 3.2Å resolution (Recacha et al., 2009). This region of Rab6IP1 encompasses an all a -helical RUN domain followed in tandem by a PLAT domain that adopts a b -sandwich fold. The structure reveals that the first and last a -helices of the RUN domain mediate binding to switch I, switch II and the interswitch region of Rab6. The structure represents the largest Rab-effector complex determined to date. Comparisons to the recent structure of Rab6 in complex with an unrelated effector, human golgin GCC185 (ref), reveals significant conformational changes in the conserved hydrophobic triad of Rab6. Thus, flexibility in the switch and interswitch regions of Rab6 mediates recognition of compositionally distinct a -helical coiled coils, thereby contributing to Rab6 promiscuity in effector recruitment.

Structure of Rab6-Rab6IP1 complex. Rab6 recruits the effector via two a-helices coming from the RUN1 domain. The all-beta PLAT domain may mediate phospholipids interactions during cargo trafficking at the level of Golgi.








The structure of the complex raises several questions. We are investigating the role of the PLAT domain in Rab6-mediated trafficking of cargo. In addition, the functional link between Rab6IP1 and Rab11 (Miserey-Lenkei et al., 2007) is currently being studied using various biochemical and structural techniques.

Bergbrede et al. (2009 ) J Biol Chem 284: 2628-2635.
Miserey-Lenkei et al. (2007) Traffic 8, 1385-1403.
Recacha R, Boulet A, Jollivet F, Monier S, Houdusse A, Goud B & Khan AR (2009) Structure 17: 21-30.



Last updated 7 September 2017 (Email).