1. Modeling the Structure of Keratin 1 and 10 Terminal Domains and their Misassembly in Keratoderma 
Cedric Badowski, Adelene Y.L. Sim, Chandra Verma, Ildikó Szeverényi, Chidambaram Natesavelalar, Ana Terron-Kwiatkowski, John Harper, Edel A. O’Toole, E. Birgitte Lane 
Journal of Investigative Dermatology 
Volume 137, Issue 9, Pages (September 2017)
DOI: /j.jid
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2. Figure 1
Subdomains within the head and tail domains of keratin 1 (K1). (a) Analysis of the K1 head domain amino acid sequence identifies five regions: two aliphatic-rich (A) regions (yellow), two regulatory (R) regions (purple), and one phenylalanine-rich (F) region (red). K1 tail contains three regions: two aliphatic-rich regions (yellow) and one tyrosine-rich (Y) region (green). (b) Position of the new A, R, F, and Y regions shown against the current subdomain nomenclature of E, V, H. D is a putative desmoplakin-binding region. (c) All-atom 3D simulation of the Y region of the K1 tail folded as a molecular spring via the π-stacking of Y lateral chains (spheres) and flexible glycine loops (rods). This spring can extend under mechanical stretch and retract on force removal.
Journal of Investigative Dermatology  , DOI: ( /j.jid )
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3. Figure 2
Keratin homotypic head-to-tail interactions form a tetrameric terminal domain complex (TTDC). (a) Homotypic head-to-tail interactions of keratin tetramers as proposed by Lu and Lane (1990). (b) The end domains of parallel heterodimers of K1/K10 (dimerizing chains connected by dotted lines) interact to form a TTDC. One dimer shown in red, and one in green. (c, d) The A1 region can interact with the A3 region by electrostatic interaction (El) between positively charged R65 of the K1 head and negatively charged E496 of the K1 tail as well as hydrophobic interactions (Ho) between their matching sequences of hydrophobic residues (L, V, I, A, P) and hydrophilic interactions (Hi) between their polar residues (S, C, N). The alignment of the two sequences requires three glycine loops. K1, keratin 1; K10, keratin 10.
Journal of Investigative Dermatology  , DOI: ( /j.jid )
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4. Figure 3
The F region of the K1 head can interact with the Y region of the K1 tail by successive intermolecular aromatic interactions forming an aromatic zipper. (a) Panels 1–6: dynamic representation of intermolecular aromatic interactions between the F residues (red spheres) of a K1 head (sections F90–F122) and the Y residues (green spheres) of a next K1 tail (sections Y525–Y559) forming an aromatic zipper. (b) The combination of the aromatic zipper between the K1 head and K1 tail and the aromatic zipper between the K10 head and K10 tail forms the tetrameric terminal domain complex (TTDC), which is stabilized by water bridges between the Y residues of the tail domains (blue asterisks). K1, keratin 1; K10, keratin 10.
Journal of Investigative Dermatology  , DOI: ( /j.jid )
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5. Figure 4
Model of the whole K1-K10 tetrameric terminal domain complex. (a) K1-K10 tail dimerization stabilized by water bridges between the Y regions (green boxes). K1 tail displays two aliphatic-rich regions (A3, A4) (yellow boxes). (b) K1-K10 head domain pairing of stacked F residues (red boxes). K1 head has two hydrophobic pockets (A1, A2, yellow boxes, G loops not represented). (c) Merging heads and tails. The F residues of the heads insert between the Y residues of the tails, whereas A1 interacts with A3, and A2 with A4. See the expanded version of this diagram in Supplementary Figure S5 and the detailed key in Supplementary Figure S6a. K1, keratin 1; K10, keratin 10; TTDC, tetrameric terminal domain complex.
Journal of Investigative Dermatology  , DOI: ( /j.jid )
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6. Figure 5
The TTDC model provides insight into the pathogenic effect of two cis deletions in K1 in a case of SPPK. (a) Clinical appearance of palmoplantar keratoderma on the patient’s hands as linear hyperkeratotic plaques. (b) Allelic variants identified as a deletion (mutation) in the K1 head and the second deletion (polymorphism) in the K1 tail. (c) The two deletions obstruct Y94 within the F-Y zipper, reducing its accessibility to kinases. Y139 and Y143 are still accessible for phosphorylation. (d) All-atom model of the FY region of the TTDC in this case of SPPK. The two deletions bring Y94 (purple) into a new position stabilized by aromatic interaction with Y525 of the K1 head and H-bonding with Y473 of the K10 head. Blue asterisks indicate sites of potential water bridges. K1, keratin 1; K10, keratin 10; SPPK, striate palmoplantar keratoderma; TTDC, tetrameric terminal domain complex.
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7. Figure 6
Model summarizing the effect of the two deletions and its link with hyperkeratosis. (a) In wild-type proteins, the molecular springs are fully extendable, and the phosphorylation of Y94 (R1 region), and Y139 and Y143 (R2 region) of K1 by kinases may facilitate keratin disassembly and remodeling in differentiating keratinocytes. (b) In this case of SPPK, the two deletions would change Y94 conformation that becomes occluded within the TTDC structure and not available for phosphorylation. This may inhibit remodeling of keratin filaments, predisposing towards disordered terminal differentiation and hyperkeratosis. K1, keratin 1; SPPK, striate palmoplantar keratoderma; TTDC, tetrameric terminal domain complex.
Journal of Investigative Dermatology  , DOI: ( /j.jid )
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