REAGENT or RESOURCE	SOURCE	IDENTIFIER
Antibodies
Mouse anti-His-647	R&D Systems	Cat#IC0501R
Penta·His Antibody; BSA free	QIAGEN	Cat#34660; RRID:AB2619735
Polyclonal Rabbit-Anti-Mouse Immunoglobulin HRP	Agilent	Cat#P0161; RRID:AB2687969
Bacterial and Virus Strains
Mix & Go Competent Cells - Strain DH5 Alpha	Zymo Research	Cat#T3007
Chemicals, Peptides, and Recombinant Proteins
2-mercaptoethanol	Thermo Fisher Scientific	Cat#21985023
4-12% Bis-Tris NuAPGE Protein Gels	Thermo Fisher Scientific	Cat#NP0322
4–20% Criterion TGX Precast Midi Protein Gel	Bio-Rad	Cat#5671095
4–20% Mini-PROTEAN® TGX Precast Protein Gels	Bio-Rad	Cat#4561096
Adenosine 5′-triphosphate disodium Salt Hydrate (ATP)	Sigma	Cat#A2383-10G
Alexa Fluor 647 NHS Ester (Succinimidyl Ester)	Thermo Fisher Scientific	Cat#A37573
Alkaline Phosphatase	Thermo Fisher Scientific	Cat#31391
Amersham ECL Prime Western Blotting Detection Reagent	Fisher Scientific	Cat#45-002-401
Antibiotic-Antimycotic Solution (100x)	Fisher Scientific	Cat#15-240-096
AscI Restriction Enzyme	New England Biolabs	Cat#R0558S
β-Nicotinamide adenine dinucleotide (NAD+) 50 mM solution	New England Biolabs	Cat#B9007S
Bicine	Sigma	Cat#B8660-100G
Bio-Safe Coomassie Stain	Bio-Rad	Cat#1610786
BirA Ligase	Özkan et al., 2013	N/A
Blotting-Grade Blocker	Bio-Rad	Cat#1706404
Bovine Serum Albumin Fraction V	Roche	Cat#03116956001
Bromophenol Blue	Fisher Scientific	Cat#BP115-25
Carbenicillin, disodium salt	Sigma	Cat#C1389-10G
cOmplete, EDTA-free Protease Inhibitor Cocktail	Sigma	Cat#5056489001
dNTP mix; 10 mM each	Genscript	Cat#C01582
d-Biotin	Sigma	Cat#B4501-5G
DTT	Sigma	Cat#D0632-25G
Expi293 Expression Medium	Thermo Fisher Scientific	Cat#A14635
ExpiFectamine	Thermo Fisher Scientific	Cat#A14635
Fetal Bovine Serum, ultra-low IgG	Thermo Fisher Scientific	Cat#16250078
FreeStyle 293 Expression Medium	Thermo Fisher Scientific	Cat#12338026
Glycerol	Fisher Scientific	Cat#BP229-4
HBS-P+ Buffer 10X	GE Healthcare	Cat#BR-1006-71
HEPES solution, 1 M, pH 7.0-7.6	Sigma	Cat#H0887
Imidazole	Acros Organics	Cat#12202-5000
InstantBlue Protein Stain	Expedeon	Cat#ISB1L
LB Agar, Miller (Powder), 2 kg	Fisher Scientific	Cat#BP1425-2
Linear Polyethylenimine	Fisher Scientific	Cat#NC9197339
Invitrogen UltraPure Agarose	Thermo Fisher Scientific	Cat#16500500
Ethidium Bromide (1% Solution), 10 mL	Fisher Scientific	Cat#BP1302-10
Luria-Bertani (LB) Broth (Miller)	Sigma	Cat#L3522-1KG
MACS buffer	Miltenyi	Cat#130-091-221
Magnesium acetate, hexahydrate	Sigma	Cat#M5661-250G
Magnesium chloride hexahydrate	Sigma	Cat#M9272-100G
MOPS NuPAGE SDS Running Buffer (20X)	Thermo Fisher Scientific	Cat#NP0001
Ni-NTA Agarose	QIAGEN	Cat#30250
NotI-HF Restriction Enzyme	New England Biolabs	Cat#R3189L
Opti-MEM Reduced Serum	Thermo Fisher Scientific	Cat#31985062
PEG-8000	Sigma	Cat#81268-1KG
Phosphate Buffered Saline, pH 7.2	GIBCO	Cat#20012-043
Phusion HF DNA Polymerase	New England Biolabs	Cat#M0530L
Propidium iodide	Thermo Fisher Scientific	Cat#P3566
Precision Plus Protein Dual Color Standards	Bio-Rad	Cat#1610374
Recombinant Human Angiopoietin-1 Protein, CF	R&D Systems	Cat#923-AN-025/CF
Recombinant Human β-NGF	R&D Systems	Cat#256-GF/CF
Recombinant Human Leptin Protein, CF	R&D Systems	Cat#398-LP-01M
Recombinant Mouse Leptin Protein, CF	R&D Systems	Cat#498-OB-01M
Recombinant protein A	Thermo Fisher Scientific	Cat#21184
SeeBlue® Plus2 Pre-stained Protein Standard	Thermo Fisher Scientific	Cat#LC5925
Series S Sensor Chip SA	GE Healthcare	Cat#BR-1005-31
Sodium bicarbonate	Fisher Scientific	Cat#BP328-500
Sodium Chloride	Fisher Scientific	Cat#S271-3
Streptavidin	Invitrogen	Cat#S888
Superdex 200 Increase column	GE Healthcare	Cat#28990944
Superose S6 column	GE Healthcare	Cat#17-5172-01
T5 Exonuclease	New England Biolabs	Cat#M0363L
Taq Ligase	New England Biolabs	Cat#M0530L
Trans-Blot® Turbo RTA Midi PVDF Transfer Kit	Bio-Rad	Cat#1704273
Tris base	Fisher Scientific	Cat#BP152-1
Tris-HCl	Fisher Scientific	Cat#BP153-1
Tween-20; Sigma	Sigma	Cat#P1379-500ML
Ultrapure SDS	Life Technologies	Cat#15525-017
Critical Commercial Assays
BCA Kit	Pierce	Cat#23227
KPL BluePhos Microwell Substrate Kit	VWR	Cat#95059-220
QIAQuick Gel Extraction Kit	QIAGEN	Cat#28506
QIAprep Spin Miniprep Kit	QIAGEN	Cat#27106
Deposited Data
Dryad	This Study	https://doi.org/10.5061/dryad.xsj3tx9bd
Experimental Models: Cell Lines
Expi 293F cells	Thermo Fisher Scientific	Cat#A14635; RRID: CVCL_D615
HEK293 Freestyle cells	Thermo Fisher Scientific	Cat#:R79007; RRID:CVCL_6642
Oligonucleotides
ISLR2 LRR1-7 forward: 5′- CTGAGCTACATCTTC TGCCTGGTGTTCGCTGCGGCCGCCTCTTGTCC TGAACCTTGTGCCTGCG-3′	This Study	N/A
ISLR2 LRR1-7 reverse: 5′- CCAGGCCC TTGAAACAGAACTTCCAACCCCGGC GCGCCAGGAGCGCAAGGCAGAGCAG-3′	This Study	N/A
ISLR2 Ig1-3 forward: 5′-CTGAGCTACATCTTC TGCCTGGTGTTCGCTGCGGCCGCCCCTAGC GTTCACCTGTCTGCC-3′	This Study	N/A
ISLR2 Ig1-3 reverse: 5′-CCAGGCCCTTGAAAC AGAACTTCCAACCCCGGCGCGCCAGAGGGC AGCTCTTTCTTGGTGC-3′	This Study	N/A
pD649-HAsp-ECD-Fc(DAPA)-AviTag-6xHis (sequencing) forward:5′-ATTTAGGTGACACTATAG-3′	This Study	N/A
pD649-HAsp-ECD-Fc(DAPA)-AviTag-6xHis (sequencing) reverse: 5′-CACGTACCAGTTGAACTTCACC-3′	This Study	N/A
Recombinant DNA
pD649-HAsp-ECD-Fc(DAPA)-AviTag-6xHis	This study	Addgene
pD649-HAsp-ECD-COMP5AP-AviTag-9xHis	This study	Addgene
pTT3-SP-6XHis-NTRK1(FL)-FLAG	This study	Addgene
pTT3-SP-6XHis-TIE1(FL)-FLAG	This study	Addgene
pTT3-SP-6XHis-PVR(FL)-FLAG	This study	Addgene
pTT3-SP-6XHis-KIR2DL5(FL)-FLAG	This study	Addgene
pTT3-SP-6XHis-KIR2DL4(FL)-FLAG	This study	Addgene
pTT3-SP-6XHis-KIR2DL1(FL)-FLAG	This study	Addgene
pTT3-SP-6XHis-ISLR2(FL)-FLAG	This study	Addgene
Software and Algorithms
Biacore T200 Control Software (version 3.2)	GE Healthcare	https://www.biacore.com/lifesciences/service/downloads/downloads/index.html
BioGRID3.5	Oughtred et al., 2019	https://thebiogrid.org/
CytExpert 2.3	Beckman Coulter	https://www.beckman.com/flow-cytometry/instruments/cytoflex/software
FlowJo 10.4.2	FlowJo	https://www.flowjo.com/
HUGO Gene Nomenclature Committee (HGNC)	Yates et al., 2017	https://www.genenames.org/
Human Protein Atlas	Uhlén et al., 2015	https://www.proteinatlas.org/
IntAct	Orchard et al., 2014	https://www.ebi.ac.uk/intact/
Interactive Tree of Life (iTOL) (version 5.5)	Letunic and Bork, 2019	https://itol.embl.de/
MAFFT (Multiple Alignment using Fast Fourier Transform)	Kuraku et al., 2013; Katoh et al., 2019	https://mafft.cbrc.jp/alignment/server/
MUltiple Sequence Comparison by Log- Expectation (MUSCLE)	Edgar, 2004	https://www.ebi.ac.uk/Tools/msa/muscle/
PredGPI	Pierleoni et al., 2008	http://gpcr.biocomp.unibo.it/predgpi/pred.htm
SignalP-5.0	Almagro Armenteros et al., 2019	http://www.cbs.dtu.dk/services/SignalP/
SnapGene 5.1	GSL Biotech LLC	https://www.snapgene.com/
STRING (version 11.0)	Szklarczyk et al., 2019
SoftMax Pro	Molecular Devices	https://www.moleculardevices.com/products/microplate-readers/acquisition-and-analysis-software/softmax-pro-software
Freedom EVOware Standard (version 2.5) Service Pack 3, Build 2.5.21.0	TECAN	https://lifesciences.tecan.com/software-freedom-evoware?
TMHMM2.0	Krogh et al., 2001	http://www.cbs.dtu.dk/services/TMHMM/
UniProt	The UniProt Consortium	https://www.uniprot.org/
Other
Econo-Pak Chromatography Column	Bio-Rad	Cat#7321011
12-Column Reservoirs	Agilent	Cat#201256-100
12-Column Reservoirs	Integra	Cat#6361
96-well deep well plates	USA Scientific	Cat#1896-2110
96-well round-bottom plate	Corning	Cat#3799
AirOtop Enhanced Seal for Ultra Yield	Fisher Scientific	Cat#NC0063892
Aluminum Foil Seals	Corning	Cat#7200684
Amicon Ultra-4 Centrifugal Filter Unit	EMD Millipore	Cat#UFC805024
Amicon Ultra-15 Centrifugal Filter Unit	EMD Millipore	Cat#UFC901024
Hyperfilm ECL	Sigma	Cat#GE28-9068-39
Nunc clear flat-bottom maxisorp 384-well plates	Thermo Fisher Scientific	Cat#464718
Nunc clear flat-bottom maxisorp 384-well plates	Thermo Fisher Scientific	Cat#464718
Nunc clear flat-bottom maxisorp 96-well plates	Thermo Fisher Scientific	Cat#442404
PolarSeal	E&K Scientific	Cat#T592100
Rapid-Flow Sterile Disposable Filter Units with PES Membrane; 250 ml (0.2 um)	Thermo Fisher Scientific	Cat#168-0045
Rapid-Flow Sterile Disposable Filter Units with PES Membrane; 50 ml (0.2 um)	Thermo Fisher Scientific	Cat#564-0020
Rapid-Flow Sterile Disposable Filter Units with PES Membrane; 1 L (0.2 um)	Thermo Fisher Scientific	Cat#567-0020
Seahorse Single Cavity P.P. Pyramid Base Reservoirs	Agilent	Cat#201244-100
TECAN TP unfiltered 200 ul tips; Zymark	MBP/Thermo Fisher Scientific	Cat#923-261
TECAN TR unfiltered 100 ul tips; Zymark	MBP/Thermo Fisher Scientific	Cat#907-261