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Girish Mali

Macromolecular motor assembly

We investigate how cells assemble large multi-subunit motor proteins called axonemal dyneins which power the rhythmic beating motion of eukaryotic cilia and flagella. Our major focus is a newly discovered family of structurally and functionally diverse proteins called Dynein Axonemal Assembly Factors/DNAAFs which shepherd the folding and assembly of individual dynein subunits into functional macromolecular motors. To uncover the molecular mechanisms of DNAAFs, we combine biochemistry, integrative structural and cell biology, and proteomic approaches.

Motile cilia are actively beating microtubular protrusions found on many cell surfaces. They enable critical biological functions ranging from sperm propulsion to clearing mucus in lungs. Loss of cilia motion results in a severe incurable disease called Primary Ciliary Dyskinesia (PCD) marked by respiratory complications at birth. Progressive decline in lung function due to inefficient mucus clearance and recurrent infections can be life-limiting. Patients also display other clinical complications including sub-fertility.

Axonemal dyneins, which come in two flavours – the inner and outer dynein arms (IDAs and ODAs), power the rhythmic beating motion of cilia. Dyneins are massive molecular motors, ex. a single ODA motor, comprised of ~20 distinct subunits, is ~2 MDa in size. How cells synthesise such large and biochemically complex machines is a fundamental cell biology question that our lab aims to address.

A novel protein family called dynein axonemal assembly factors/DNAAFs shepherd dynein biosynthesis from their folding to final transport into cilia. DNAAFs are structurally distinct and functionally non-redundant i.e., loss of any one of the nineteen DNAAFs found in humans can derail the entire biosynthetic pathway leading to PCD. Several DNAAFs bind one another and cooperate with chaperone proteins to facilitate dynein biosynthesis but the molecular details of how DNAAFs function are still unclear.

PCD remains incurable. Uncovering the underlying pathology to find new treatments requires mechanistic studies on DNAAFs. This is the lab’s major goal – to dissect the molecular and structural basis of axonemal dynein assembly by DNAAFs. For this, we integrate cell biology (fluorescence microscopy, endogenous cellular proteomics), biochemistry (complex isolation, reconstitutions) and structural biology (negative stain and cryo-electron microscopy, AlphaFold2 structure predictions). We are open to enquiries from prospective PhD students (via the Dunn School’s DPhil in Molecular Cell Biology in Health and Disease.), summer students and postdocs (aiming to obtain independent fellowships).