There is as yet no high-resolution data regarding the structure and organization 
of keratin intermediate filaments, which are obligate heteropolymers providing 
vital mechanical support in epithelia. We report the crystal structure of 
interacting 2B regions from the central coiled-coil domains of keratins 5 and 14 
(K5 and K14), expressed in progenitor keratinocytes of epidermis. The interface 
of the K5-K14 coiled-coil heterodimer has asymmetric salt bridges, hydrogen 
bonds and hydrophobic contacts, and its surface exhibits a notable charge 
polarization. A trans-dimer homotypic disulfide bond involving Cys367 in K14's 
stutter region occurs in the crystal and in skin keratinocytes, where it is 
concentrated in a keratin filament cage enveloping the nucleus. We show that 
K14-Cys367 impacts nuclear shape in cultured keratinocytes and that mouse 
epidermal keratinocytes lacking K14 show aberrations in nuclear structure, 
highlighting a new function for keratin filaments.