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molecular basis of disorder

PDB_2fft_EBI.jpg

Cartoon representation of the molecular structure of protein registered with 2fft code. By Jawahar Swaminathan and MSD staff at the European Bioinformatics Institute – Public Domain, https://commons.wikimedia.org/w/index.php?curid=5877319

Intrinsically disordered proteins are thought to be fully functional, yet do not confirm to a single conformation, thereby identifying their structure via crystallography becomes problematic. Many intrinsically disordered proteins have been studied and analyzed using NMR methods, however the question as to why proteins are intrinsically disordered is still debatable.

While, viewing X-ray diffraction data some residues do not have an electron density region, thus they are marked as missing residues. These regions are highly mobile and are considered as intrinsically disordered. For some proteins, the entire sequence is considered intrinsically disordered.

ResearchBlogging.orgIt is a widely accepted fact that sequence dictates structure, and structure in turn dictates function. So, is the “disordered-ness” encoded in the genome, if so to what extent? This and related questions have led Basile et al at the Stockholm University, Sweden to delve deeper and have narrowed it down to GC content. Their work has been published in latest issue of PLoS Computational Biology.

Using computational methods they analyzed 400 eukaryotic genomes and looked into the so-called orphan genes, specifically. They categorized the age of the proteins using ProteinHistorian tool and looked into the old and young proteins. They found that the

…selective pressure to change amino acids in a protein is stronger than the one to change the GC content. At low GC ancient proteins are more disordered than expected for random sequence while at high GC they are less.

The three disorder promoting amino acids (Ala, Pro, and Gly) are high in GC content w.r.t to their codons. However,

At high GC the youngest proteins become more disordered and contain less secondary structure elements, while at low GC the reverse is observed. We show that these properties can be explained by changes in amino acid frequencies caused by the different amount of GC in different codons.

References:

  1.  Basile, W., Sachenkova, O., Light, S., & Elofsson, A. (2017). High GC content causes orphan proteins to be intrinsically disordered PLOS Computational Biology, 13 (3) DOI: 10.1371/journal.pcbi.1005375

There is a Native American or African belief that when one travels for long distance, the body moves physcially at a faster rate to the new geographic location, but the soul takes its own time to catch up [1, 2]. I am sure traveling to conferences at international venues, or a trip back home (journey from Americas to Asia) can cause severe jet-lag in most of us.

Well, I don’t know about souls, but I do know that being jet lag is the same as getting sick. It is ironic, that the protein responsible for this is called SIK1, short for Salt-inducible protein kinase 1. I don’t know what others are pronouncing it, I like to say it as ‘sick-one’! 🙂

COURBET, Gustave The Sleeping Spinner 1853 Oil on canvas, 91 x 115 cm Musée Fabre, Montpellier

COURBET, Gustave The Sleeping Spinner 1853
Oil on canvas, 91 x 115 cm
Musée Fabre, Montpellier

Jagannath et al [3] in the latest issue of Cell reported the stealth activity of SIK1 acting on a negative-feedback mechanism. It inhibits another protein’s expression, called per1. It is part of the CRTC1 pathway The key mechanism is phosphorylation of the “core-clock proteins”, thus making a time-delayed process of adjusting. There is a logical reason as to why SIK1 would limit other protein’s function. Our human physiology has internal mechanisms that protect our functionality from sudden changes, specifically the one that have huge impact. In this case, even if the internal clock could get adjusted within a 24 hr cycle, there would be chaos as “multiple cell-autonomous circadian oscillators” would not have sped up to match.

ResearchBlogging.orgUsing in-vitro and in-vivo methods Jagannath et al have found the key protein, that can be targeted. You might think “Wait. Didn’t you just now say that this a coping mechanism of the body?”. Yes, I did. There are people who suffer from circadian rhythm abnormalities called SCRD [4]. In such cases, patients suffer from impaired cognition, metabolic disorders, immune dysfunction and also cancer.

Here are SIK1’s Uniprot and NCBI links. It is a 783 amino acids long protein, where the N-terminus has the kinase domain, and the C-terminal part has a Arg-Ser rich region. That only the kinase domain could be homology-modeled was obvious. The C-terminal part lacking any homology to other sequences. The N-terminal looks like, after homology-modeling. Image made using PyMOL from ModBase model.

Here is the BBC report on this work.

Homology modeled N-terminal of SIK1

Homology modeled N-terminal of SIK1

References:

  1. http://womenswritingcenter.wordpress.com/2009/06/01/waiting-for-my-soul-to-catch-up/
  2. http://teacherleaders.typepad.com/tln_teacher_voices/2006/06/letting_our_sou.html
  3. Aarti Jagannath, Rachel Butler, Sofia I.H. Godinho, Yvonne Couch, Laurence A. Brown, Sridhar R. Vasudevan, Kevin C. Flanagan, Daniel Anthony, Grant C. Churchill, Matthew J.A. Wood, Guido Steiner, Martin Ebeling, Markus Hossbach, Joseph G. Wettstein, Giles E. Duffield, Silvia Gatti, Mark W. Hankins, Russell G. Foster, & Stuart N. Peirson1 (2013). The CRTC1-SIK1 Pathway Regulates Entrainment of the Circadian Clock Cell, 154 (5), 1100-1111 DOI: 10.1016/j.cell.2013.08.004
  4. http://en.wikipedia.org/wiki/Circadian_rhythm_sleep_disorder#Circadian_rhythm_abnormalities
  5. http://www.ncbi.nlm.nih.gov/gene/150094
  6. http://www.uniprot.org/uniprot/P57059
  7. http://www.bbc.co.uk/news/health-23880152