Dynamics and Allostery in Ferritin

bpj_109_6_3cWe all know it is important to get the proper amount of iron in our diet. If the protein that processes iron isn’t properly functioning, this aphorism is just that.  The protein responsible for this is called Ferritin, a 24 subunit protein whose functions is the oxidation and storage of iron. Disruption of ferritin can lead to a whole host of ailments from cataracts to Alzheimer’s disease.

The cover image is a ribbon diagram of human ferritin (PDBID 3AJO) colored by its dynamic flexibility index (DFI) profile, a measure of each residue’s contribution to a protein’s dynamics, where blue is the lowest (most rigid) and red is the highest (most flexible). Traditionally, proteins were thought to obey the sequence-structure-function paradigm—the function of a protein is embedded in its structure. The new paradigm is the sequence-structure encoded-dynamics-functions paradigm—a protein’s structure encodes its dynamics, which encodes its function, leading to a deeper understanding of protein function. We have found that disruption of dynamic allosteric residue coupling of residues in ferritin leads to impaired protein function. There are certain rigid parts of the protein that function as hinges, transmitting motion. If a mutation, which is further away from the hinge site, allosterically loosens the hinge, then the protein cannot properly transmit motion, breaking the dynamics, thus breaking the function. This is similar to the hinge of a door. If the hinge gets loosened, motion will not be properly transmitted and the door cannot function properly.

The DFI metric has led to advancements in understanding the fluorescence of GFP, finding new functions through protein evolution in betalactamase, and computational prediction of functional impact of non-synonymous single nucleotide polymorphisms observed in human populations. Using DFI analysis, we have investigated how the function diverged for a given protein family, while maintaining the same exact fold/ structure.  Comparing the DFI profiles of different members of the same protein family shows that mutations leading to shifts in hinge sites alter the dynamics, thus the function (1,2).  Our proteome-wide conformational dynamics analysis using DFI indicates that certain sites play a critical role in functionally related dynamics (i.e., those with low dfi values), therefore, mutations at those sites are more likely to be associated with disease (3,4)

– Avishek Kumar, Tyler Glembo, Sefika Ozkan


  • Zou T, Risso VA, Gavira JA, Sanchez-Ruiz JM, Ozkan SB “Evolution of Conformational Dynamics Determines the Conversion of a Promiscuous Generalist into a Specialist Enzyme”. (2015) Mol Biol. Evol. 32:132-143.
  • Kim H, Zou T, Modi C, Dorner K, Grunkmeyer TJ, Chen L, Fromme R, Matz MV, Ozkan SB, Wachter RM, “A hinge migration mechanism unlocks the evolution of green-to-red photoconversion in GFP-like proteins”. (2015) Structure , 23:34-43
  • Butler MA, Gerek ZN, Kumar S and Ozkan SB “Dynamically critical sites at protein interface are more prone to disease” (2015) Proteins, 83:428-435
  • Gerek ZN, Kumar S and Ozkan SB* Structural dynamics flexibility informs function and evolution at a proteome scale” (2013) Evol Appl. 6:4223-4332. doi: 10.1111/eva.12052

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