for RNA transport, processing localization, SG
assembly, and epithelial cell differentiation due
to the numerous keratins enriched in LARKS.
Therefore, we propose 3D profiling for LARKS
as a tool to identify proteins that may form networks and gels by multivalent interactions and
may participate in membraneless organelles
In conclusion, the prevalence of LCDs within
eukaryotic proteomes has long been recognized
(30), but the role of these domains has not been
fully defined. Previous discoveries include the
following: LCDs can “functionally aggregate” (31);
proteins with LCDs typically form more protein-
protein interactions (32, 33); and proteins can
interact homotypically and heterotypically through
LCDs (1, 5, 34). Our atomic structures support the
hypothesis that LCDs have the capacity to form
gel-like networks. LARKS possess three properties
that are consistent with their functioning as ad-
hesive elements in protein gels formed from LCDs:
(i) high aqueous solubility contributed by their
high proportion of hydrophilic residues: serine,
glutamine, and asparagine; (ii) flexibility ensured
by their high glycine content; and (iii) multiple
interaction motifs per chain (Fig. 3B), endow-
ing them with multivalency, enabling them to en-
tangle, forming networks as found in gels (Fig. 2).
That each LARKS provides adhesion only com-
parable to thermal energy suggests that numerous
LARKS must cooperate in gel formation and that
the interactions must be concentration dependent
and may be transient. If steric zippers act as mo-
lecular glue, then LARKS in LCDs act as Velcro.
These properties are compatible with the hypo-
thesis that LARKS are a protein interaction motif
that provides adhesion of LCDs in protein gels and
in membraneless assemblies (fig S10).
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D.S.E. is on the scientific advisory board and holds equity in
ADRx, Inc. X-ray diffraction data were collected at the
Northeastern Collaborative Access Team beamline 24-ID-E,
which is funded by the National Institute of General Medical
Sciences from the National Institutes of Health (P41
GM103403). This research used resources of the Advanced
Photon Source, a U.S. Department of Energy (DOE) Office of
Science User Facility operated for the DOE Office of Science by
Argonne National Laboratory under contract no. DE-AC02-
06CH11357. We thank NSF MCB-1616265, NIH AG-054022, DOE,
and HHMI for support. Atomic coordinates and structure
factors have been deposited in the PDB with the following
accession codes: SYSGYS (6BWZ), SYSSYGQS (6BXV),
STGGYG (6BZP), GYNGFG (6BXX), and GFGNFGTS (6BZM).
Materials and Methods
Figs. S1 to S10
Tables S1 to S3
13 May 2017; resubmitted 15 November 2017
Accepted 4 January 2018