Abstract
Keratin intermediate filaments constitute the primary cytoskeletal component of epithelial cells. Numerous human disease phenotypes related to keratin mutation remain mechanistically elusive. Our recent crystal structures of the helix 1B heterotetramer from keratin 1/10 enabled further investigation of the effect of pathologic 1B domain mutations on keratin structure. We used our highest resolution keratin 1B structure as a template for homology-modeling the 1B heterotetramers of keratin 5/14 (associated with blistering skin disorders), keratin 8/18 (associated with liver disease), and keratin 74/28 (associated with hair disorder). Each structure was examined for the molecular alterations caused by incorporating pathogenic 1B keratin mutations. Structural modeling indicated keratin 1B mutations can harm the heterodimer interface (R265PK5, L311RK5, R211PK14, I150VK18), the tetramer interface (F231LK1, F274SK74), or higher-order interactions needed for mature filament formation (S233LK1, L311RK5, Q169EK8, H128LK18). The biochemical changes included altered hydrophobic and electrostatic interactions, and altered surface charge, hydrophobicity or contour. Together, these findings advance the genotype-structurotype-phenotype correlation for keratin-based human diseases.
Highlights
Intermediate filaments (IFs) work with actin microfilaments and microtubules to provide essential cytoskeleton functions within eukaryotic cells
We used our highest resolution K1/K10 1B structure to model 1B domains of K5/K14, K8/K18, and Keratin 74 (K74)/K28 in order to evaluate the structural alterations associated with pathogenic keratin missense mutations in this region
We identified 15 mutations: 9 missense, 3 nonsense, 2 leading to frameshift, and 1 in-frame deletion (Table 1)
Summary
Intermediate filaments (IFs) work with actin microfilaments and microtubules to provide essential cytoskeleton functions within eukaryotic cells. There are six types of IFs [2], with type I and II representing keratins. Parallel heterodimers form anti-parallel tetramers, which serve as the building block for mature IFs. Keratins are differentially expressed across human tissues, providing unique biological functions to support the host organism. Different keratin mutations are responsible for blistering skin disorders (e.g., epidermolysis bullosa simplex, EBS), keratodermas (e.g., epidermolytic palmoplantar keratoderma, EPPK), hair and nail defects (e.g., pachyonychia congenita), and liver disease (e.g., cryptogenic cirrhosis) [6]. We used our highest resolution K1/K10 1B structure to model 1B domains of K5/K14, K8/K18, and K74/K28 in order to evaluate the structural alterations associated with pathogenic keratin missense mutations in this region. We wanted to ascertain whether the mutations would impact the dimer, tetramer, or high-order assembly of the keratins, and how the mutations would affect the molecular surface properties (charge, hydrophobicity, contour) of the keratins
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