The uses of disorder in the cell

We know that many proteins have disordered segments, and an older (2004) estimate says that over 30% of all eukaryotic proteins have disordered stretches of more than 30 amino acids.  Here is another example where the disordered conformation(s) of a protein is the form used by the cell.

Histone H1 (aka the linker histone) binds to DNA between nucleosomes.  It is thought to be important in the 10,000 or so compaction of the 3 meters or so of DNA each cell has so it fits into a 10 micron nucleus.  Histone H1 has a disordered carboxy terminal tail of 100 amino acids.  Unsurprisingly it is strongly positively charged (so it binds to the negatively charged phosphates holding DNA together).

H1 was studied in an interesting paper [ Proc. Natl. Acad. Sci. vol. 115 pp. 11964 – 11969 ’18 ].  The tail was added to short (36 basepairs) double stranded segment of DNA, under various stoichiometries and ionic compositions.  They found regions where the complex formed liquid droplets the size of microns.

We know DNA is compacted and people have looked for the 30 nanoMeter DNA fiber of DNA bound to nucleosomes for years without success.  It is possible that the compaction in DNA is due to phase separation (which is basically unstructured) rather than the rather specific structures proposed.  H1 may be acting as a likquidlike glue.  Fascinating.

In other work H1 was complexed with another protein (Prothymosin alpha) which is another intrinsically disordered protein which actually serves as a histone H1 chaperone.  Prothymosin is is polyAnionic, so it binds to polyCationic H1.  What is fascinating is that the binding is quite tight (picoMolar) and yet even when so tightly bound H1 remains disordered, something to confound drug chemists who are always looking for specific binding conformations.

The paper also describes Psi DNA, which is formed in solutions of cationic polymers. Here DNA condenses into a compact solvent excluded state.  It is an ordered assembly of B-DNA arranged in parallel twisted helical segments with a well define spacing.  It produces an anomalously large scattering signal in circular dichroism spectra.

Here is an older post in which the functional form of a protein is the unstructured one

When the active form of a protein is intrinsically disordered

Back in the day, biochemists talked about the shape of a protein, influenced by the spectacular pictures produced by Xray crystallography. Now, of course, we know that a protein has multiple conformations in the cell. I still find it miraculous that the proteins making us up have only relatively few. For details see —

Presently, we also know that many proteins contain segments which are intrinsically disordered (e.g. no single shape).The pendulum has swung the other way — “estimations that contiguous regions longer than 50 amino acids ‘may be present” in ‘up to’ 50% of proteins coded in eukaryotic genomes [ Proc. Natl. Acad. Sci. vol. 102 pp. 17002 – 17007 ’05 ]

[ Science vol. 325 pp. 1635 – 1636 ’09 ] Compared to ordered regions, disordered regions of proteins have evolved rapidly, contain many short linear motifs that mediate protein/protein interactions, and have numerous phosphorylation sites compared to ordered regions. Disordered regions are enriched in serine and threonine residues, while ordered sequences are enriched in tyrosines — this highlights functional differences in the types of phosphorylation. Interestingly tyrosines have been lost during evolution.

What are unstructured protein segments good for? One theory is that the disordered segment can adopt different conformations to bind to different partners — this is the moonlighting effect. Then there is the fly casting mechanism — by being disordered (hence extended rather than compact) such proteins can flail about and find partners more easily.

Given what we know about enzyme function (and by inference protein function), it is logical to assume that the structured form of a protein which can be unstructured is the functional form.

Not so according to this recent example [ Nature vol. 519 pp. 106 – 109 ’15 ]. 4EBP2 is a protein involved in the control of protein synthesis. It binds to another protein also involved in synthesis (eIF4E) to suppress a form of translation of mRNA into protein (cap dependent translation if you must know). 4EBP2 is intrinsically disordered. When it binds to its target it undergoes a disorder to ordered transition. However eIF4E binding only occurs from the intrinsically disordered form.

Control of 4EBP2 activity is due, in part, to phosphorylation on multiple sites. This induces folding of amino acids #18 – #62 into a 4 stranded beta domain which sequesters the canonical YXXXLphi motif with which 4EBP2 binds eIF4E (Y stands for tyrosine, X for any amino acid, L for leucine and phi for any bulky hydrophobic amino acid). So here we have an inactive (e.g. nonbonding) form of a protein being the structured rather than the unstructured form. The unstructured form of 4EBP2 is therefore the physiologically active form of the protein.

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