Evolution and disorder

The evolution of disordered proteins or regions of proteins differs from that of ordered proteins because of the differences in their sequence composition, intramolecular contacts, and function. Recent assessments of disordered protein evolution at the sequence, structural, and functional levels support this hypothesis. Disordered proteins have a different pattern of accepted point mutations, exhibit higher rates of insertions and deletions, and generally, but not always, evolve more rapidly than ordered proteins. Even with these high rates of sequence evolution, a few examples have shown that disordered proteins maintain their flexibility under physiological conditions, and it is hypothesized that they maintain specific structural ensembles.     

Borderline personality disorder

BORDERLINE PERSONALITY DISORDER is a chronic psychiatric disorder characterized by marked impulsivity, instability of mood and interpersonal relationships, and suicidal behaviour that can complicate medical care. Identifying this diagnosis is important for treatment planning. Although the cause of borderline personality disorder is uncertain, most patients improve with time. There is an evidence base for treatment using both psychotherapy and psychopharmacology. The clinical challenge centres on managing chronic suicidality.CaseColleen, a 22-year old student, is seen for a psychiatric assessment after presenting to the emergency department because of taking an overdose of acetaminophen pills. Although the immediate precipitant to her suicide attempt was a break-up with her boyfriend, she has a history of multiple suicide attempts since the age of 14. Colleen reports that she has daily mood swings, from depression to intense anger, and that she often cuts herself on the wrists and arms to relieve dysphoria. When stressed, she experiences feelings of unreality, sometimes hearing a voice telling her to kill herself. Colleen has had highly problematic relationships with men, falling quickly in and out of love and feeling that her life depends on them, even when they have behaved abusively toward her. What is the appropriate diagnosis and management of this patient?Personality disorders constitute a major group in the classification of mental disorders. According to the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR),¹ these conditions are defined by maladaptive personality characteristics beginning early in life that have consistent and serious effects on functioning. Borderline personality disorder (BPD) is frequently seen in clinical practice.² Characterized by emotional turmoil and chronic suicidality (suicide ideation and attempts), this type of personality disorder presents some of the most difficult and troubling problems in all of psychiatry.     

Protein disorder prediction by condensed PSSM considering propensity for order or disorder

Background  

More and more disordered regions have been discovered in protein sequences, and many of them are found to be functionally significant. Previous studies reveal that disordered regions of a protein can be predicted by its primary structure, the amino acid sequence. One observation that has been widely accepted is that ordered regions usually have compositional bias toward hydrophobic amino acids, and disordered regions are toward charged amino acids. Recent studies further show that employing evolutionary information such as position specific scoring matrices (PSSMs) improves the prediction accuracy of protein disorder. As more and more machine learning techniques have been introduced to protein disorder detection, extracting more useful features with biological insights attracts more attention.     

Structural disorder in proteins

The refinement of X-ray structural data gives the mean square displacements, x ², at each position in the protein molecule. In order to get information on the significance of such values different refinement methods have been compared. The metmyoglobin structure was determined at 300 K and x ²-values were obtained with the restrained refinement procedure in reciprocal space of Konnert and Hendrickson. A comparison with the results of Frauenfelder et al. was used for an error estimation. The inclusion of surface bound water increases the accuracy of the results but does not change the general picture. For erythrocruorin (CTT3) a refinement was performed in reciprocal space and compared with a refinement in real space performed earlier. The x ²-values obtained from both procedures are similar although the reciprocal space refinement gives results which are physically more reasonable.A comparison of the disorder in myoglobin and erythrocruorin showed that the structural similarity results in a similarity in the disorder. Contacts of molecules in the crystal do not dominate the disorder although they locally influence x ²-values. CTT3 shows large disorder in the heme region in contrast to myoglobin. The differences in the rigidity of the F-helix can be correlated with the oxygen affinities supporting models for O₂ binding developed by Frauenfelder et al.     

A lead-induced behavioral disorder

Mice were exposed to lead from birth by substituting solutions of lead acetate (2, 5, and 10 mg/ml) for the drinking water of mice 12 hours after parturition. Controls received equal concentrations of sodium acetate. There were no deaths in mothers or offspring due to treatment, but growth and development were retarded in the lead-treated offspring. It has recently been suggested that lead exposure may account for some incidences of hyperactivity and retardation in children. Activity of offspring was measured between 40 and 60 days of age for four consecutive days. Treated mice were more than three times as active as age-matched controls. These studies show that chronic ingestion of lead can produce a significant behavior disorder in mice.     

Myeloproliferative disorder by TKO

In this issue of Cell Stem Cell, Viatour et al. (2008) delete all three members of the retinoblastoma tumor suppressor gene family in hematopoietic stem cells, resulting in a myeloproliferative disorder. The disease was cell autonomous and resulted from alterations in the primitive hematopoietic cells.     

Flavors of protein disorder

Intrinsically disordered proteins are characterized by long regions lacking 3-D structure in their native states, yet they have been so far associated with 28 distinguishable functions. Previous studies showed that protein predictors trained on disorder from one type of protein often achieve poor accuracy on disorder of proteins of a different type, thus indicating significant differences in sequence properties among disordered proteins. Important biological problems are identifying different types, or flavors, of disorder and examining their relationships with protein function. Innovative use of computational methods is needed in addressing these problems due to relative scarcity of experimental data and background knowledge related to protein disorder. We developed an algorithm that partitions protein disorder into flavors based on competition among increasing numbers of predictors, with prediction accuracy determining both the number of distinct predictors and the partitioning of the individual proteins. Using 145 variously characterized proteins with long (>30 amino acids) disordered regions, 3 flavors, called V, C, and S, were identified by this approach, with the V subset containing 52 segments and 7743 residues, C containing 39 segments and 3402 residues, and S containing 54 segments and 5752 residues. The V, C, and S flavors were distinguishable by amino acid compositions, sequence locations, and biological function. For the sequences in SwissProt and 28 genomes, their protein functions exhibit correlations with the commonness and usage of different disorder flavors, suggesting different flavor-function sets across these protein groups. Overall, the results herein support the flavor-function approach as a useful complement to structural genomics as a means for automatically assigning possible functions to sequences.