Structure and Aggregation

Ribbon model showing folded and unfolded amyloid
Top and middle: Tau protein can reversibly change conformation to hide and expose the 6-peptide amyloid motif (blue) that plays a critical role in pathological aggregation. Once exposed, the amyloid motif drives the irreversible formation of tangles in brain tissue (bottom).

Traditionally, proteins have been regarded as rigid structures, whose final form was predicated on their amino acid sequence. But recent research has shown that some proteins are highly flexible in both shape and function.

As these intrinsically disordered proteins (IDPs) morph into particular shapes, they hide or reveal local regions that are biologically active. Several disease-related proteins, including tau, are IDPs.

We are focused on a section of tau called the "amyloid motif," a sequence of six amino acids that drives tau aggregation and pathology. The motif becomes physically inaccessible and biologically inactive in some conformations of tau.

We hypothesize that sequences near the amyloid motifs inhibit protein aggregation, and that these elements play essential roles in controlling aggregation properties of IDPs.

Our lab uses a combination of bioinformatics, structural dynamics, and biophysical techniques to study the various shapes of tau, which shapes prevent or allow pathological aggregation, and which are the key local regions within tau.

We have recently demonstrated that disease-causing mutations in tau protein localize near its amyloid motif where they perturb local secondary structure and drive aggregation.

Our ongoing work is to identify which elements within tau prevent amyloid formation, and determine what features are necessary to stabilize these non-aggregating forms.


Chen, D, et al. (2019). Tau local structure shields an amyloid-forming motif and controls aggregation propensity. Nat Comm 10, 2493.