TY - JOUR
T1 - Presence and structure-activity relationship of intrinsically disordered regions across mucins
AU - Carmicheal, Joseph
AU - Atri, Pranita
AU - Sharma, Sunandini
AU - Kumar, Sushil
AU - Chirravuri Venkata, Ramakanth
AU - Kulkarni, Prakash
AU - Salgia, Ravi
AU - Ghersi, Dario
AU - Kaur, Sukhwinder
AU - Batra, Surinder K.
N1 - Publisher Copyright:
© 2020 Federation of American Societies for Experimental Biology
PY - 2020/2/1
Y1 - 2020/2/1
N2 - Many members of the mucin family are evolutionarily conserved and are often aberrantly expressed and glycosylated in various benign and malignant pathologies leading to tumor invasion, metastasis, and immune evasion. The large size and extensive glycosylation present challenges to study the mucin structure using traditional methods, including crystallography. We offer the hypothesis that the functional versatility of mucins may be attributed to the presence of intrinsically disordered regions (IDRs) that provide dynamism and flexibility and that the IDRs offer potential therapeutic targets. Herein, we examined the links between the mucin structure and function based on IDRs, posttranslational modifications (PTMs), and potential impact on their interactome. Using sequence-based bioinformatics tools, we observed that mucins are predicted to be moderately (20%-40%) to highly (>40%) disordered and many conserved mucin domains could be disordered. Phosphorylation sites overlap with IDRs throughout the mucin sequences. Additionally, the majority of predicted O- and N- glycosylation sites in the tandem repeat regions occur within IDRs and these IDRs contain a large number of functional motifs, that is, molecular recognition features (MoRFs), which directly influence protein-protein interactions (PPIs). This investigation provides a novel perspective and offers an insight into the complexity and dynamic nature of mucins.
AB - Many members of the mucin family are evolutionarily conserved and are often aberrantly expressed and glycosylated in various benign and malignant pathologies leading to tumor invasion, metastasis, and immune evasion. The large size and extensive glycosylation present challenges to study the mucin structure using traditional methods, including crystallography. We offer the hypothesis that the functional versatility of mucins may be attributed to the presence of intrinsically disordered regions (IDRs) that provide dynamism and flexibility and that the IDRs offer potential therapeutic targets. Herein, we examined the links between the mucin structure and function based on IDRs, posttranslational modifications (PTMs), and potential impact on their interactome. Using sequence-based bioinformatics tools, we observed that mucins are predicted to be moderately (20%-40%) to highly (>40%) disordered and many conserved mucin domains could be disordered. Phosphorylation sites overlap with IDRs throughout the mucin sequences. Additionally, the majority of predicted O- and N- glycosylation sites in the tandem repeat regions occur within IDRs and these IDRs contain a large number of functional motifs, that is, molecular recognition features (MoRFs), which directly influence protein-protein interactions (PPIs). This investigation provides a novel perspective and offers an insight into the complexity and dynamic nature of mucins.
KW - glycoprotein
KW - intrinsically disordered protein
KW - protein structure
KW - protein–protein interaction
UR - http://www.scopus.com/inward/record.url?scp=85078802414&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85078802414&partnerID=8YFLogxK
U2 - 10.1096/fj.201901898RR
DO - 10.1096/fj.201901898RR
M3 - Article
C2 - 31908009
AN - SCOPUS:85078802414
SN - 0892-6638
VL - 34
SP - 1939
EP - 1957
JO - FASEB Journal
JF - FASEB Journal
IS - 2
ER -