Open Positions:

Applications open for the following options,

Undergraduate positions via

– DAAD-WISE Fellowship 2025 (undergraduate level)

PhD positions via

– Boehringer Ingelheim Fonds Stiftung für medizinische Grundlagenforschung

Postdoctroal positions via

– Humboldt Fellowship

– Walter Benjamin Fellowship

Collagens are a large family of proteins found in skin, bone, cartilage, teeth, blood vessels and cornea.¹ All collagen proteins contain a characteristic domain called a triple helix, which is rod-like motif composed of three polypeptides. The triple-helices form fibres, mesh and filaments. ² At the macromolecular level, these provide strength and elasticity to the skin, support the rigid structure of bone and teeth and regulate the shape and transparency of cornea. At the molecular level, they interact with cell-surface proteins to regulate cell adhesion, proliferation and migration and also secreted blood serum proteins to facilitate blood clotting. In this context, our lab investigates the following two fundamental questions related to collagen (bio)chemistry.

How do collagens fold?

Triple-helical peptides fold via a nucleation-zipper mechanism, in which three peptides nucleate at the C-termini and progressively fold into a triple helix like a zip chain. By extrapolation, a similar mechanism is believed to operate in native collagens. However, this leaves several questions unanswered. First, given their stupendous length (> 1000 amino acids), how do collagen polypeptides overcome the enormous entropic cost of folding? Second, polypeptides in the native triple helix are staggered by one amino. How do collagens avoid incorrect staggers during folding? And finally, collagen sequences come in two flavours; those containing uninterrupted Gly-Xaa-Yaa repeats and those in which this perfect repeat pattern is interrupted with non-collagenous sequences. Interruptions structurally perturb triple helices and alter stability and folding kinetics. During zipping from C- to N-termini, how do collagens re-nucleate after an interruption while also maintaining correct chain alignment? A collagen-specific chaperone heat shock protein 47 (HSP47) binds to unique sites in collagens as they are folding. This is believed to prevent local unfolding and prevent incorrect staggered alignment. However, we contend that the information for correct folding of collagens in encoded in the sequence.

We bioinformatically analyze the natural collagen sequence to identify sequence motifs that appear more frequently than others. We then introduce these motifs into synthetic collagen triple helices obtained via peptide synthesis and investigate their thermodynamic and kinetic stability as well as folding kinetics. The end goal is to understand how frequency and abundance of such motifs dictates the speed and fidelity of collagen folding in the endoplasmic reticulum.

How do collagens recognize other proteins?

Collagen genes encode 46 polypeptides that assemble into 28 distinct triple-helices (col1-28). These act as ligands for a wide variety of other proteins to regulate homeostasis and thrombosis. Frequently, these proteins recognize more than one collagen subtypes but with distinct specificity. Molecular investigation of this specificity is crucial from a physiological and therapeutic perspective but this is not straightforward. Collagen subtypes come in three flavours: triple helices containing either identical (homotrimer), two dissimilar chains (AAB-type heterotrimers) or all unique chains (ABC-type heterotrimers). The interaction of collagen to other proteins is widely studied using peptides that mimic the triple-helical structure. This approach works well for homotrimers due to the intrinsic ability of collagen-peptides to self-trimerize. In contrast, obtaining heterotrimers is technically challenging due the possibility of self- and cross-trimerization. We address this challenge by designing heterotrimeric mimics of natural collagens and using them to understanding the collagen binding specificity of three proteins;

• cell-adheion receptors integrin α1β1, α2β1, α10β1 and α11β1 which together recognize at least eight different collagen subtypes.
• discoidin domain receptors (DDR) 1 and 2, which together recognize seven different collagen subtypes
• blood serum protein Von Willebrand Factor, which is a multidomain protein recognizing at least five different collagen subtypes.